Gonadal dysgenesis

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Gonadal dysgenesis
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Diagnostic method pelvic 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), family history
Treatmentsurgery

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. [1] [2] One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. [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]

Contents

Gonadal development is a process, which is primarily controlled genetically by the chromosomal sex (XX or XY), which directs the formation of the gonad (ovary or testicle). [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 phenotype corresponding to the karyotype (46,XX for females and 46,XY for males). [5]

Gonadal dysgenesis arises from a difference in 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 causes. [7]

Causes

Pathogenesis

46,XX 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 the body 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

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 penis and scrotum. [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 undifferentiated [15] [16] [17] which are then differentiated via androgen's and SRY activation. [18]

Full undermasculinization results in a fully developed vulva with testicles inside the body 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. [19] [20]

SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation. [21] 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, [22] with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis persons. [21]

Mixed gonadal dysgenesis

Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis, [21] is a sex development difference 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. [23]

The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype. [21] [23]

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. [22] [23]

The dysgenic testis can have an amount of functional tissue which can produce a level of testosterone, which causes masculinisation. [22] [23]

Mixed gonadal dysgenesis is poorly understood at the molecular level. [23] The loss of the Y chromosome can occur from deletions, translocations, or migration diffenernce of paired chromosomes during cell division. [22] [23] The chromosomal loss results in partial expression of the SRY gene, giving rise to atypical development of the reproductive tract and altered hormone levels. [22] [23]

Turner syndrome

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] [24] [25] giving a chromosomal count of 45, instead of the typical count of 46 chromosomes. [24]

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] [24] Normal ovarian development requires these vital regions of the X chromosome that are inactivated. [4] [26] Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility, and failure to develop secondary sex characteristics. [25] 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. [23] Comorbidities include heart defects, vision and hearing problems, diabetes, and low thyroid hormone production. [4] [25]

Endocrine disruptions

Endocrine disruptors interfere with the endocrine system and hormones. [27] Hormones are critical for the common events in embryogenesis to occur. [26] 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. [28]

Diagnosis

Management

History

Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938. [29] 46,XX pure gonadal dysgenesis was first reported in 1960. [29] 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955. [29]

See also

Related Research Articles

<span class="mw-page-title-main">XY sex-determination system</span> Method of determining sex

The XY sex-determination system is a sex-determination system present in many mammals, including humans, some insects (Drosophila), some snakes, some fish (guppies), and some plants.

<span class="mw-page-title-main">Gonad</span> Gland that produces sex cells

A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm in the form of spermatozoa. The female gonad, the ovary, produces egg cells. Both of these gametes are haploid cells. Some hermaphroditic animals have a type of gonad called an ovotestis.

<span class="mw-page-title-main">XY gonadal dysgenesis</span> Medical condition

XY complete gonadal dysgenesis, also known as Swyer syndrome, is a type of defect hypogonadism in a person whose karyotype is 46,XY. Though they typically have normal vulvas, the person has underdeveloped gonads, fibrous tissue termed "streak gonads", and if left untreated, will not experience puberty. The cause is a lack or inactivation of an SRY gene which is responsible for sexual differentiation. Pregnancy is sometimes possible in Swyer syndrome with assisted reproductive technology. The phenotype is usually similar to Turner syndrome (45,X0) due to a lack of X inactivation. The typical medical treatment is hormone replacement therapy. The syndrome was named after Gerald Swyer, an endocrinologist based in London.

<span class="mw-page-title-main">Persistent Müllerian duct syndrome</span> Medical condition

Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives in what would be considered a genetically and otherwise physically normal male animal by typical human based standards. In humans, PMDS typically is due to an autosomal recessive congenital disorder and is considered by some to be a form of pseudohermaphroditism due to the presence of Müllerian derivatives. PMDS can also present in non-human animals.

<span class="mw-page-title-main">Sex-determining region Y protein</span> Protein that initiates male sex determination in therian mammals

Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male sex determination in therian mammals. SRY is an intronless sex-determining gene on the Y chromosome. Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype.

<span class="mw-page-title-main">Male reproductive system</span> Reproductive system of the human male

The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body, and within the pelvis.

<span class="mw-page-title-main">XX male syndrome</span> Congenital condition where an individual with a 46,XX karyotype is male

XX male syndrome, also known as de la Chapelle syndrome, is a rare intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms for XX male syndrome include 46,XX testicular difference of sex development

Ovotesticular syndrome is a rare congenital condition where an individual is born with both ovarian and testicular tissue. It is one of the rarest DSDs, with only 500 reported cases. Commonly, one or both gonads is an ovotestis containing both types of tissue. Although it is similar in some ways to mixed gonadal dysgenesis, the conditions can be distinguished histologically.

<span class="mw-page-title-main">Sex cords</span> Structures that develop from the genital ridges that further differentiate based on an embryos sex

Sex cords are embryonic structures which eventually will give rise (differentiate) to the adult gonads. They are formed from the genital ridges - which will develop into the gonads - in the first 2 months of gestation which depending on the sex of the embryo will give rise to male or female sex cords. These epithelial cells penetrate and invade the underlying mesenchyme to form the primitive sex cords. This occurs shortly before and during the arrival of the primordial germ cells (PGCs) to the paired genital ridges. If there is a Y chromosome present, testicular cords will develop via the Sry gene : repressing the female sex cord genes and activating the male. If there is no Y chromosome present the opposite will occur, developing ovarian cords. Prior to giving rise to sex cords, both XX and XY embryos have Müllerian ducts and Wolffian ducts. One of these structures will be repressed to induce the other to further differentiate into the external genitalia.

<span class="mw-page-title-main">Genital ridge</span> Developmental precursor to the gonads in an embryo

In embryology, the genital ridge is the developmental precursor to the gonads. The genital ridge initially consists mainly of mesenchyme and cells of underlying mesonephric origin. Once oogonia enter this area they attempt to associate with these somatic cells. Development proceeds and the oogonia become fully surrounded by a layer of cells.

<span class="mw-page-title-main">XX gonadal dysgenesis</span> Medical condition

XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in a person assigned female at birth, whose karyotype is 46,XX. Individuals with XX gonadal dysgenesis have normal-appearing external genitalia as well as Müllerian structures. Due to the nearly absent or nonfunctional streak ovaries, the individual is low in estrogen levels (hypoestrogenic) and has high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), hormones that cycle in the reproductive system. As a result, the diagnosis often occurs after a concern for delayed puberty or amenorrhea. Treatment generally involves hormone replacement therapy with estrogen and progesterone.

<span class="mw-page-title-main">Sexual differentiation in humans</span> Process of development of sex differences in humans

Sexual differentiation in humans is the process of development of sex differences in humans. It is defined as the development of phenotypic structures consequent to the action of hormones produced following gonadal determination. Sexual differentiation includes development of different genitalia and the internal genital tracts and body hair plays a role in sex identification.

Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism", a condition describing an individual with both female and male reproductive gonadal tissues. Associated conditions includes Persistent Müllerian duct syndrome and forms of androgen insensitivity syndrome.

<span class="mw-page-title-main">Disorders of sex development</span> Medical conditions involving the development of the reproductive system

Disorders of sex development (DSDs), also known as differences in sex development or variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical. DSDs is a clinical term used in some medical settings for what are otherwise referred to as intersex traits. The term was first introduced in 2006 and has not been without controversy.

<span class="mw-page-title-main">Steroidogenic factor 1</span> Protein-coding gene in humans

The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.

<span class="mw-page-title-main">WNT4</span> Protein-coding gene in the species Homo sapiens

WNT4 is a secreted protein that, in humans, is encoded by the WNT4 gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function may have consequences, such as female to male sex reversal.

46,XX/46,XY is either a chimeric or mosaic genetic condition characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype in a single human being. While some individuals with this condition may be classified as intersex, others may have typical male or female characteristics.

<span class="mw-page-title-main">Leydig cell hypoplasia</span> Medical condition

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is a fairly rare chromosomal disorder at birth, with an estimated incidence rate of about 1 in 15,000 live births. Mosaic loss of the Y chromosome in previously non-mosaic men grows increasingly common with age.

Sexual anomalies, also known as sexual abnormalities, are a set of clinical conditions due to chromosomal, gonadal and/or genitalia variation. Individuals with congenital (inborn) discrepancy between sex chromosome, gonadal, and their internal and external genitalia are categorised as individuals with a disorder of sex development (DSD). Afterwards, if the family or individual wishes, they can partake in different management and treatment options for their conditions. Many intersex people are engaged in activism to stop such treatments, citing the extreme and harmful nature of many of the treatments, further arguing that many of the treatments serve no medical purpose.

References

  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. Vol. 135. Elsevier Health Sciences. pp. 662–685. doi:10.1016/B978-1-4160-4090-3.X5001-7. ISBN   9781416040903. PMC   1491552 .{{cite book}}: |journal= ignored (help)
  3. ↑ "Gonadal Streak. Farlex Partner Medical Dictionary".
  4. 1 2 3 4 5 6 7 8 9 10 11 Balsamo A, Buonocore G, Bracci R, Weindling M (2012). "Disorders of Sexual Development". Neonatology. Springer.
  5. 1 2 3 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. 1 2 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. 1 2 3 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. 1 2 3 4 5 6 7 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. 1 2 3 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. 1 2 3 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. 1 2 3 4 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. ↑ Rey, Rodolfo; Josso, Nathalie; Racine, Chrystèle (2000), Feingold, Kenneth R.; Anawalt, Bradley; Blackman, Marc R.; Boyce, Alison (eds.), "Sexual Differentiation", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID   25905232 , retrieved 27 May 2024
  16. ↑ Gilbert, Scott F. (2000), "Chromosomal Sex Determination in Mammals", Developmental Biology. 6th edition, Sinauer Associates, retrieved 27 May 2024
  17. ↑ Digital, G. L. P. (21 September 2017). "Embryos aren't female by 'default' after all, study shows". Genetic Literacy Project. Retrieved 27 May 2024.
  18. ↑ Kusz, Kamila; Kotecki, Maciej; Wojda, Alina; Szarras-Czapnik, Maria; Latos-Bielenska, Anna; Warenik-Szymankiewicz, Alina; Ruszczynska-Wolska, Anna; Jaruzelska, Jadwiga (1 June 1999). "Incomplete masculinisation of XX subjects carrying the SRY gene on an inactive X chromosome". Journal of Medical Genetics. 36 (6): 452–456. doi:10.1136/jmg.36.6.452. PMC   1734388 . PMID   10874632 – via jmg.bmj.com.
  19. ↑ "Variation in Sex Characteristics". www.healthit.gov. Archived from the original on 14 May 2023. Retrieved 5 August 2023.
  20. ↑ Alice D. Dreger; April M. Herndon. "Progress and Politics in the intersex rights movement, Feminist theory in action" (PDF).
  21. 1 2 3 4 Biason-Lauber A (2006). "The Battle of the Sexes: Human Sex Development and Its Disorders". 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.
  22. 1 2 3 4 5 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.
  23. 1 2 3 4 5 6 7 8 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.
  24. 1 2 3 "Turner Syndrome: Condition Information". Eunice Kennedy Shriver National Institute of Health and Human Development. 2012.
  25. 1 2 3 Saenger P, Bondy A (2014). "Turner Syndrome". Pediatric Endocrinology (4th ed.). pp. 664–696. ISBN   9780323315258.
  26. 1 2 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.
  27. ↑ "Endocrine Disruptors, National Institute of Environmental Health Sciences, 2013".
  28. ↑ Robert S (2010). "Pesticide atrazine can turn male frogs into females". Berkeley News, University of California.
  29. 1 2 3 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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