Gonadal dysgenesis

46,XX gonadal dysgenesis is characteristic of female hypogonadism with a karyotype of 46,XX.[8] Streak ovaries are present with non-functional tissues unable to produce the required sex steroid oestrogen.[9] Low levels of oestrogen effect the HPG axis with no feedback to the anterior pituitary to inhibit the secretion of FSH and LH.[9]

FSH and LH are secreted at elevated levels.[9] Increased levels of these hormones will cause to not start puberty, not undergo menarche, and not develop secondary sex characteristics.[9][10] If ovarian tissue is present and produces some amount of hormones, limited menstrual cycles can occur.[9]

46,XX gonadal dysgenesis can manifest from a variety of causes.[6] Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of changes in the FSH receptor[10][11] and mutations in steroidogenic acute regulatory protein (StAR protein) which regulates steroid hormone production.[10]

46,XY gonadal dysgenesis is characteristic of male hypogonadism with karyotype 46,XY.[12] In embryogenesis, the development of the male gonads is primarily controlled by the testis determining factor located on the sex-determining region of the Y chromosome (SRY).[12] The male gonad is dependent on SRY and the signalling pathways initiated to several other genes to facilitate testis development.[9]

The aetiology of 46,XY gonadal dysgenesis can be caused by mutations in the genes involved in testis development such as SRY, SOX9, WT1, SF1, and DHH.[9][13] If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to atypical male external genitalia.[14]

Genital Undermasculinization is the technical term for partial of complete undifferentiated genitallia in individuals with an SRY gene. In utero all fetuses are anatomically female which are then differentiated via androgen's and SRY activation.[15]

Full undermasculinization results in fully external female genitalia and internal testis where the ovaries usually are, which is caused by conditions such as complete androgen insensitivity syndrome. In 5α-Reductase 2 deficiency individuals are born with normal female genitalia, however during puberty male differentiation and spermatogenesis occurs. Partial genital undermasculinization can occur if the body has a partial resistance to androgens, or if genital development is blocked, undermasculization can also be induced by certain drugs and hormones. The overall intensity of undermasculinization can manifest itself in hypospadias. The surgical assignment of newborns with ambiguous genitalia to a binary sex for cosmetic purposes is considered a human rights violation.[16][17]

SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation.[18] An absence in SRY causes SOX9 to not be expressed at the usual time or concentration, leading to a decreased testosterone and anti-Müllerian hormone production.[4]

Lowered levels of testosterone and anti-Müllerian hormone disrupts the development of Wolffian ducts and internal genitalia that are key to male reproductive tract development.[4] The absence of the steroid hormones commonly associated with males drives Müllerian duct development and promotes the development of female genitalia, if anti-Müllerian hormone is suppressed or the body is insensitive, persistent Müllerian duct syndrome occurs when the individual has partial female reproductive, and partial male reproductive organs.[12]

Gonadal streaks can replace the tissues of testes, resembling ovarian stroma absent of follicles.[14] 46,XY gonadal dysgenesis can remain unsuspected until delayed pubertal development is observed.[14] Approximately 15% of cases of 46,XY gonadal dysgenesis carry de novo mutations in the SRY gene,[19] with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis persons.[18]

Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis,[18] is a sex development differnece associated with sex chromosome aneuploidy and mosaicism of the Y chromosome.[14] Mixed gonadal dysgenesis is the presence of two or more germ line cells.[20]

The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype.[18][20]

Manifestations of mixed gonadal dysgenesis are highly variable with asymmetry in gonadal development of testis and streak gonad, accounted for by the percentage of cells expressing XY genotype.[19][20]

The dysgenic testis can have an amount of functional tissue which can produce a level of testosterone, which causes masculinisation.[19][20]

Mixed gonadal dysgenesis is poorly understood at the molecular level.[20] The loss of the Y chromosome can occur from deletions, translocations, or migration diffenernce of paired chromosomes during cell division.[19][20] The chromosomal loss results in partial expression of the SRY gene, giving rise to atypical development of the reproductive tract and altered hormone levels.[19][20]

Turner syndrome, also known as 45,X or 45,X0, is a chromosomal abnormality characterised by a partial or completely missing second X chromosome,[4][21][22] giving a chromosomal count of 45, instead of the typical count of 46 chromosomes.[21]

Dysregulation in meiosis signalling to germ cells during embryogenesis may result in nondisjunction and monosomy X from not occurred separation of chromosomes in either the parental gamete or during early embryonic divisions.[4][7]

The aetiology of Turner syndrome phenotype can be the result of haploinsufficiency, where a portion of critical genes are rendered inactive during embryogenesis.[4][21] Normal ovarian development requires these vital regions of the X chromosome that are inactivated.[4][23] Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility, and failure to develop secondary sex characteristics.[22] Turner syndrome is usually not diagnosed until a delayed onset of puberty with Müllerian structures found to be in infantile stage.[4] Physical phenotypic characteristics include short stature, dysmorphic features and lymphedema at birth.[20] Comorbidities include heart defects, vision and hearing problems, diabetes, and low thyroid hormone production.[4][22]

Endocrine disruptors interfere with the endocrine system and hormones.[24] Hormones are critical for the common events in embryogenesis to occur.[23] Foetal development relies on the proper timing of the delivery of hormones for cellular differentiation and maturation.[4] Disruptions can cause sexual development disorders leading to gonadal dysgenesis.[25]