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 abnormal elevated levels.[9] Improper levels of these hormones will cause a failure to initiate puberty, undergo menarche, and develop secondary sex characteristics.[9][10] If sufficient functional ovarian tissue is present, limited menstrual cycles can occur.[9]

The pathogenesis of 46,XX gonadal dysgenesis is unclear, as it can manifest from a variety of dysregulations.[6] Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of abnormalities 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 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 malformation of male external genitalia.[14]

SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation.[15] An absence in SRY causes SOX9 to not be expressed at the appropriate time or concentration, leading to a deficiency in testosterone and anti-Müllerian hormone production.[4]

Inadequate 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 lack of the male associated steroid hormones drives Müllerian duct development and promotes the development of female genitalia.[12]

Gonadal streaks replace the tissues of the 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,[16] with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis patients.[15]

Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis,[15] is a sex development disorder 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.[17]

The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype.[15][17]

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.[16][17]

The dysgenic testis can have adequate functional tissue to produce satisfactory levels of testosterone to cause masculinisation.[16][17]

Mixed gonadal dysgenesis is poorly understood at the molecular level.[17] The loss of the Y chromosome can occur from deletions, translocations, or migration failure of paired chromosomes during cell division.[16][17] The chromosomal loss results in partial expression of the SRY gene, giving rise to abnormal development of the reproductive tract and altered hormone levels.[16][17]

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][18][19] giving a chromosomal count of 45, instead of the typical count of 46 chromosomes.[18]

Dysregulation in meiosis signalling to germ cells during embryogenesis may result in nondisjunction and monosomy X from separation failure 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][18] Normal ovarian development requires these vital regions of the X chromosome that are inactivated.[4][20] Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility, and failure to develop secondary sex characteristics.[19] Turner syndrome is 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.[17] Comorbidities include heart defects, vision and hearing problems, diabetes, and low thyroid hormone production.[4][19]

Endocrine disruptors interfere with the endocrine system and hormones.[21] Hormones are critical for the correct events in embryogenesis to occur.[20] 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.[22]