Gonadal dysgenesis

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Gonadal dysgenesis
SpecialtyMedical genetics Edit this on Wikidata
Diagnostic methodpelvic examination (checking for maturation of external internal genitals), general examination (looking for secondary sexual characters), chromosome karyotyping, hormone levels like FSH, LH (which are increased in case of purely XX dysgenesis)

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system[1] in the male or female. It is the atypical development of the gonads in an embryo,[2] with reproductive tissue replaced with functionless, fibrous tissue, termed streak gonads.[3] Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.[4]

Gonadal development is a genetically controlled process by the chromosomal sex (XX or XY) which directs the formation of the gonad (ovary or testis).[4]

Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events.[5] At the formation of the developed gonad, steroid production influences local and distant receptors for continued morphological and biochemical changes.[5] This results in the appropriate phenotype corresponding to the karyotype (46,XX for females and 46,XY for males).[5]

Gonadal dysgenesis arises from the failure of signalling in this tightly regulated process during early foetal development.[6][7]

Manifestations of gonadal dysgenesis are dependent on the aetiology and severity of the underlying defect.[7]



46,XX gonadal dysgenesis[edit]

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[edit]

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[edit]

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[edit]

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 disruptions[edit]

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]




Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938.[23] 46,XX pure gonadal dysgenesis was first reported in 1960.[23] 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955.[23]

See also[edit]


  1. ^ Carreau S, Lejeune H (2001). "Andrology: Male Reproductive Health and Dysfunction". Andrologie. 11 (2): 95–97. doi:10.1007/BF03034401.
  2. ^ Hughes I (2008). "The Testes: Disorders of Sexual Differentiation and Puberty in the Male". Pediatric Endocrinology. Canadian Medical Association Journal. Vol. 135. Elsevier Health Sciences. pp. 662–685. doi:10.1016/B978-1-4160-4090-3.X5001-7. ISBN 9781416040903. PMC 1491552.
  3. ^ "Gonadal Streak. Farlex Partner Medical Dictionary".
  4. ^ a b c d e f g h i j k Balsamo A, Buonocore G, Bracci R, Weindling M (2012). "Disorders of Sexual Development". Neonatology. Springer.
  5. ^ a b c Pieretti RV, Donahoe PK (2018). "Pathogenesis and Treatment of Disorders of Sexual Development". Endocrine Surgery in Children. Springer. pp. 241–270. doi:10.1007/978-3-662-54256-9_18. ISBN 978-3-662-54254-5.
  6. ^ a b Boizet-Bonhoure B (2015). "Development and Pathology of the Gonad". Seminars in Cell & Developmental Biology. 45: 57–58. doi:10.1016/j.semcdb.2015.11.009. PMID 26653403.
  7. ^ a b c Jorgensen A, Johansen M, Juul A, Skakkebaek N, Main K, Rajpert-De Meyts E (2015). "Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development". Seminars in Cell & Developmental Biology. 45: 124–137. doi:10.1016/j.semcdb.2015.09.013. PMID 26410164.
  8. ^ Quayle S, Copeland K (1991). "46, XX Gonadal Dysgenesis With Epibulbar Dermoid". American Journal of Medical Genetics. 40 (1): 4075–4076. doi:10.1002/ajmg.1320400114. PMID 1909490.
  9. ^ a b c d e f g Nieschlag E, Behre H, Wieacker P, Meschede D, Kamischke A, Kliesch S (2010). "Disorders at the Testicular Level". Andrology. Springer. pp. 193–238. doi:10.1007/978-3-540-78355-8_13. ISBN 978-3-540-78355-8.
  10. ^ a b c Grimbly C, Caluseriu O, Metcalfe P, Jetha M, Rosolowsky E (2016). "46, XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing". International Journal of Pediatric Endocrinology. 12: 12. doi:10.1186/s13633-016-0030-x. PMC 4908721. PMID 27307783.
  11. ^ Aittomaki K, Lucena J, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila E (1995). "Mutations in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure". Cell. 82 (6): 959–968. doi:10.1016/0092-8674(95)90275-9. PMID 7553856. S2CID 14748261.
  12. ^ a b c Chen H, Huang H, Chang T, Lai C, Soong Y (2006). "Pure XY gonadal dysgenesis and agenesis in monozygotic twins". Fertility and Sterility. 85 (4): 1059.9–1059.11. doi:10.1016/j.fertnstert.2005.09.054. PMID 16580399.
  13. ^ Barseghyan H, Symon A, Zadikyan M, Almalvez M, Segura E, Eskin A, Bramble M, Arboleda V, Bazter R, Nelson S, Delot E, Harley V, Vilain E (2018). "Identification of novel candidate genes for 46, XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model". Biology of Sex Differences. 9 (8): 8. doi:10.1186/s13293-018-0167-9. PMC 5789682. PMID 29378665.
  14. ^ a b c d Han Y, Wang Y, Li Q, Dai S, He A, Wang E (2011). "Dysgerminoma in a case of 46, XY pure gonadal dysgenesis (Swyer Syndrome): a case report". Diagnostic Pathology. 6 (84): 84. doi:10.1186/1746-1596-6-84. PMC 3182960. PMID 21929773.
  15. ^ a b c d Biason-Lauber A (2006). The Battle of the Sexes: Human Sex Development and Its Disorders in Molecular Mechanisms of Cell Differentiation in Gonad Development. Results and Problems in Cell Differentiation. Vol. 58. pp. 337–382. doi:10.1007/978-3-319-31973-5_13. ISBN 978-3-319-31971-1. PMID 27300185.
  16. ^ a b c d e Bashamboo A, McElreavey K (2015). "Human sex-determination and disorders of sex-development (DSD)". Seminars in Cell & Developmental Biology. 45: 77–83. doi:10.1016/j.semcdb.2015.10.030. PMID 26526145.
  17. ^ a b c d e f g h Donahoe P, Crawford J, Hendren W (1979). "Mixed Gonadal Dysgenesis, Pathogenesis and Management". Journal of Pediatric Surgery. 14 (3): 287–300. doi:10.1016/s0022-3468(79)80486-8. PMID 480090.
  18. ^ a b c "Turner Syndrome: Condition Information". Eunice Kennedy Shriver National Institute of Health and Human Development. 2012.
  19. ^ a b c Saenger P, Bondy A (2014). "Turner Syndrome". Pediatric Endocrinology (4th ed.). pp. 664–696. ISBN 9780323315258.
  20. ^ a b Elsheikh M, Dunger D, Conway G, Wass J (2002). "Turners Syndrome in adulthood". Endocrine Reviews. 23 (1): 120–140. doi:10.1210/edrv.23.1.0457. PMID 11844747.
  21. ^ "Endocrine Disruptors, National Institute of Environmental Health Sciences, 2013".
  22. ^ Robert S (2010). "Pesticide atrazine can turn male frogs into females". Berkeley News, University of California.
  23. ^ a b c Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M (2015). "Perspectives in Pediatric Pathology, Chapter 5. Gonadal Dysgenesis". Pediatr. Dev. Pathol. 18 (4): 259–78. doi:10.2350/14-04-1471-PB.1. PMID 25105336. S2CID 20122694.

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