In foetal sexual differentiation

Normal male sexual development is dependent both on genetic events of gonadal development as well as on endocrine pathways initiated by hormones secreted from the testes (Fig. 3.2). Gonadal differentiation is initiated with the development of the bipotent gonad during early embryonal life (Hiort and Holterhus 2000). Several genes are known to be involved in this process leading to the creation of the undifferentiated gonad. Abnormalities in the Wilms tumour 1 (WT1) gene are associated with failure of gonadal differentiation, nephropathy, development of Wilms tumours (Denys-Drash syndrome and Frasier syndrome), and in the WAGR syndrome which also involves anomalies of the eye (aniridia) and mental retardation.

Another gene involved in the development of the bipotential gonad and the kidneys is the recently cloned LIMl-gene. Homozygous deletions in this gene in mice lead to developmental failure of both gonads and kidneys. To date, no human mutations have been described in this gene, although a phenotype of renal and gonadal developmental defects in association with brain abnormalities might be anticipated. The role of the steroidogenic factor 1 (SF1) in the formation of the gonad is not yet clear. SF1 is the product of the FTZl-Fl-gene and is believed to be a nuclear orphan hormone receptor due to the presence of two zinc fingers and a ligand binding domain in its molecular structure. FTZ1-F1 mRNA is expressed in the urogenital ridge which forms both gonads and adrenals, and is also found in developing brain regions. Mice lacking SF1 fail to develop gonads, adrenals, and the hypothalamus. However, SF1 is probably also involved in other aspects of sexual development, as it regulates the expression of steroidogenic enzymes as well as the transcription of the anti-Mullerian hormone (AMH) (Ozisik etal. 2003).

Further progession of gonadal differentiation from the bipotential gonad is mediated through gonosomal and autosomal genes. It was long believed and has been proven that a specific testis-determining-factor (TDF) was essential for testicular development and that the encoding gene was located on the Y-chromosome. This gene, termed sex-determining-region of the Y-chromosome (SRY) is a single-exon gene which encodes a protein with a DNA-binding motif that acts as a transcription factor and in turn regulates the expression of other genes. Evidence was provided that SRY binds to the promoter of the AMH gene and also controls the expression of steroidogenic enzymes (Harley et al. 2003). Thus, SRY probably induces the expression of AMH to prevent the formation of Mullerian duct derivatives. Evidence that SRY is the TDF was presented when the mouse homologue SRY gene was introduced into the mouse germ line and genetic female offspring showed a normal male phenotype in these genetically engineered animals (Koopman et al. 1991). Furthermore, naturally occurring mutations of SRY have been described in humans (Hiort etal. 1995).

Autosomal genes which are structurally related to SRY genes have been described. These 'SRY-box-related' or SOX-genes are to some extent involved in testicular development. SOX 9 is connected with chondrogenesis and gonadal differentiation. This gene is transcribed especially following SRY-expression in male gonadal structures. Additionally, SOX 9 is an activator of the type II collagen gene which in turn is essential for formation of the extracellular matrix of cartilage (Harley et al. 2003). A gene which is involved in adrenal as well as in ovarian and testicular development is DAX1. This gene is located on the X-chromosome and was termed:

Dosage-sensitive sex reversal locus - Adrenal hypoplasia congenita - critical region on the X, gene 1. DAX 1 is expressed during ovarian development, but is silent during testis formation, implying a critial role in ovarian formation. Interestingly, DAX-1 is repressed by SRY during testicular development. However, if a duplication of the DAX-1 region on Xp21 is present in a 46,XY patient and, thus, the activity of its gene product is enhanced, testicular formation is impaired. In contrast, mutations in DAX-1 diminishing its activity lead to a lack of adrenal formation and also hypogonadal hypogonadism in congenital adrenal hypoplasia (Beuschlein et al. 2002). Further genes involved in testicular differentiation have been localized on chromosome 10 and on chromosome 9 (DMRT 1 and 2).

In early gestation, both the anlagen for the Wolffian and Mullerian ducts are present in the foetus regardless of the karyotype. If testicular formation is unhindered, the Sertoli cell will produce AMH. To exert the action of AMH, high concentrations of this hormone and active binding to a membrane receptor in the mes-enchymal cells surrounding the Mullerian ducts are necessary. Therefore, reduced excretion of AMH due to lowered number of Sertoli cells is responsible for partial uterus formation disorders of sex determination. The AMH gene is under tran-scriptional control of several other proteins involved in sexual differentiation. SF-1 binds directly to the AMH gene promoter and activates its transcription in the Sertoli cells. A regulatory effect of SRY on AMH receptor expression has also been reported (Lim and Hawkins 1998).

Unhindered steroid hormone formation and action is necessary for the development ofthe external genitalia. Furthermore, defects in cholesterol synthesis may also lead to distinct phenotypes including deficiencies of genital development. The first steps of steroid biosynthesis are common pathways for glucocorticoids, mineralo-corticoids, and sex steroids, while the formation of testosterone from androstene-dione via 176-hydroxysteroid dehydrogenase type 3 is probably limited to testis (Hiort etal. 2000). In contrast, further conversion of testosterone to DHT is catalysed in the peripheral target tissues and not within the gonads. Androgen synthesis in the developing testes is controlled during early foetal life by human chorionic gonadotropin (hCG) and only later by the foetal luteinizing hormone (LH) itself.

Expression of the AR is present even prior to the onset of testicular androgen secretion. There is a marked similarity in distribution and intensity of AR staining in the external genitalia of male and female fetuses at 18 to 22 weeks gestation (Kalloo etal. 1993), a finding that explains the virilization of female fetuses when exposed to supranormal androgen concentrations as in congenital adrenal hyperplasia.

The major sites of action are the virilization of the male accessory glands and the male external genitalia. Testosterone may act differently in this process. Paracrine actions of high concentrations of testosterone result in differentiation of the Wolffian duct, thus forming the deferent ducts. Endocrine actions are caused by testosterone which reaches its target tissues, e.g. the external male genitalia, via the blood stream. Depending on the anatomical region, testosterone can be further converted to dihydrotestosterone. Both testosterone and dihydrotestosterone enter the target cells and bind to the cytoplasmic AR. The AR belongs to the nuclear receptor superfamily and is a ligand activated transcription factor of androgen regulated genes (Hiort and Holterhus 2000). Binding of the ligand induces an activation cascade involving dissociation of the receptor from heat shock proteins, receptor phosphorylation, dimerization, translocation of the receptor into the nucleus, interaction with specific hormone responsive elements within the promoter region of androgen regulated genes and assembly of the basal transcription machinery finally resulting in specific gene transcription. Binding of the androgenic ligand to the AR is a highly specific event (Poujol etal. 2000). While earlier studies stressed the well-described fact that dihydrotestosterone is a much stronger ligand for the AR than testosterone (Deslypere et al. 1992), more recent data suggest that this concept needs qualitative extension. Hsiao etal. (2000) recently identified different androgen response elements which showed a differential response upon activating the AR through either testosterone or dihydrotestosterone. Moreover, recently it was demonstrated that structurally different androgens with different profiles of biological actions induced very different response patterns through the AR when using three structurally different androgen responsive promoters in co-transfection assays (Holterhus etal. 2002). The morphogenetic result of these specific actions of androgens is the irreversible virilization of the external male genitalia. This process is terminated in the 12th week of gestation. Hence, incomplete masculinization, e.g., incomplete closure of the midline (hypospadias) during the sensitive window between the 7th and the 12th week cannot be overcome by even high doses of androgens at later stages of development. This fact may seem trivial but it clearly indicates that the genomic programs provided by the androgen target tissues must have undergone comprehensive and definitive alterations in parallel to the ontogenetic process of external virilization.

Vanish Man Boobs

Vanish Man Boobs

Say goodbye to embarrassing man boobs forever. Thats right. Im going to share all of the research I collected and the cures I found with you. It is entirely possible to cure your man boobs forever without the use of drugs or surgery. Im going to show you how.

Get My Free Ebook

Post a comment