Gonadal dysgenesis

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Gonadal dysgenesis
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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

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system [1] in humans. It is atypical development of gonads in an embryo. [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 female which are then differentiated via androgen's and SRY activation. [15]

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. [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

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

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 disruptions

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]

Diagnosis

Management

History

Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938. [26] 46,XX pure gonadal dysgenesis was first reported in 1960. [26] 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955. [26]

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 used to classify many mammals, including humans, some insects (Drosophila), some snakes, some fish (guppies), and some plants. In this system, the sex of an individual is determined by a pair of sex chromosomes. In most cases, females have two of the same kind of sex chromosome (XX), and are called the homogametic sex. Males have two different kinds of sex chromosomes (XY), and are called the heterogametic sex.

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

A gonad, sex gland, or reproductive gland is a mixed gland 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 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 often 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">Paramesonephric duct</span> Paired ducts in the embryo in the primitive urogenital structures

The paramesonephric ducts are paired ducts of the embryo in the female reproductive system that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fallopian tubes, uterus, cervix, and the upper one-third of the vagina.

<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.

<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 congenital intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms include 46,XX testicular difference of sex development, 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.

<span class="mw-page-title-main">Ovotesticular syndrome</span> Intersex condition including both ovarian and testicular tissue

Ovotesticular syndrome is a term for an intersex condition in which an individual is born with both ovarian and testicular tissue. 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>

The genital ridge is the 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.

XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in an otherwise normal girl whose karyotype is found to be 46,XX. With nonfunctional streak ovaries, she is low in estrogen levels (hypoestrogenic) and has high levels of FSH and LH. Estrogen and progesterone therapy is usually then commenced. Some cases are considered a severe version of premature ovarian failure where the ovaries fail before puberty.

<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 a condition in which an individual has a matching chromosomal and gonadal tissue sex, but mismatching external genitalia.

<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 variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.

<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 a chimeric 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. The cause of the condition lies in utero with the aggregation of two distinct blastocysts or zygotes into a single embryo, which subsequently leads to the development of a single individual with two distinct cell lines, instead of a pair of fraternal twins. 46,XX/46,XY chimeras are the result of the merging of two non-identical twins. This is not to be confused with mosaicism or hybridism, neither of which are chimeric conditions. Since individuals with the condition have two cell lines of the opposite sex, it can also be considered an intersex condition.

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.

References

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  25. ↑ Robert S (2010). "Pesticide atrazine can turn male frogs into females". Berkeley News, University of California.
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