Sexual anomalies

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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). [1] Afterwards, if the family or individual wishes, they can partake in different management and treatment options for their conditions (e.g. hormone therapy).

Contents

Infants born with atypical genitalia often cause confusion and distress for the family. Psychosexual development is influenced by numerous factors that include, but are not limited to, gender differences in brain structure, genes associated with sexual development, prenatal androgen exposure, interactions with family, and cultural and societal factors. [2] Because of the complex and multifaceted factors involved, communication and psychosexual support are all important.

A team of experts, or patient support groups, are usually recommended for cases related to sexual anomalies. This team of experts are usually derived from a variety of disciplines including pediatricians, neonatologists, pediatric urologists, pediatric general surgeons, endocrinologists, geneticists, radiologists, psychologists and social workers. [3] [4] [5] These professionals are capable of providing first line (prenatal) and second line diagnostic (postnatal) tests to examine and diagnose sexual anomalies.

Overview

Chemical structure of testosterone Testosterone.PNG
Chemical structure of testosterone

In the normal prenatal stages of fetal development, the fetus is exposed to testosterone - albeit more in male fetuses than female ones. Upon the presence of the 5α-reductase enzyme, testosterone is converted to dihydrotestosterone (i.e. DHT). If DHT is present, the male external genitalia will develop.

Development of male external genitalia:

On the other hand, if maternal placenta estrogen is present without DHT, then the development of female external genitalia occurs.[ citation needed ]

Development of female external genitalia (the vulva):

Chemical structure of dihydrotestosterone (DHT) 5b-Dihydrotestosterone.svg
Chemical structure of dihydrotestosterone (DHT)

However, in abnormal cases, sexual anomalies occur due to a variety of factors that lead to an excess of androgens in the fetus. The effects of excessive androgens differ in fetuses with XX chromosome (female) and XY chromosomes (male).

In XX chromosome fetuses, excess androgens result in ambiguous genitalia. This makes identification of external genitalia as male or female difficult. [9] Additionally, the individual may have clitoromegaly, a shallow vagina, early and rapid growth of pubic hair in childhood, delayed puberty, hirsutism, virilisation, irregular menstrual cycle in adolescence and infertility due to anovulation. [10]

In XY chromosome fetuses, excess androgens result in a functional and average-sized penis with extreme virilisation, but the inability for sperm production. [11] Additionally, the individual will also experience early and rapid growth of pubic hair during childhood and precocious puberty stages. [10]

Classification

Differences/disorders of sexual development (DSD) are classified into different categories: chromosomal variation, gonadal development disorders, abnormal genital development and others.

Chromosomal variation

The symptoms of Klinefelter's syndrome in a human male. Klinefelter's syndrome.jpg
The symptoms of Klinefelter's syndrome in a human male.

DSDs caused by chromosomal variation generally do not present with genital ambiguity. This includes sex chromosome DSDs such as Klinefelter syndrome, Turner syndrome and 45,X or 46,XY gonadal dysgenesis. [12]

Males with Klinefelter syndrome usually have a karyotype of 47,XXY as a result of having two or more X chromosomes. [13] Affected patients generally have normal genital development, yet are infertile and have small, poor functioning testes, breast growth and delayed puberty. [13] The incidence for 47,XXY is 1 in 500 males, but severe and rare cases of Klinefelter syndrome presents as three or more X chromosomes. [13]

Turner syndrome is classified as aneuploidy or structural rearrangement of the X chromosome. Signs and symptoms of affected females vary among them, such as low birth weight, low-set ears, short stature, short neck and delayed puberty. [14] The incidence is 1 in 2500 live-born females, while most patients do not survive for more than one year after birth. [12]

Gonadal development disorders

Gonadal development disorders form a wide spectrum, classified by their cytogenetic and histopathological features. However, unsolved diagnosis and malignancy still represent difficulties in the sex determination of these patients. [15] Such disorders include partial or complete gonadal dysgenesis, ovotesticular DSD, testicular DSD and sex reversal. [3]

Abnormal genital development

Genital abnormality can occur in the penis, scrotum or testes in males; and vagina and labia in females. [3] Sometimes, ambiguous genitalia could occur, where the clear distinction of external genitalia is absent in both male and female. Hence, examination (typically at birth) is carried out where the sex of the patient will be determined through imaging and blood tests. [3] Abnormal genital development includes disorders of fetal origin, disorders in androgen synthesis or action, disorders in anti-Müllerian hormone synthesis or action. [3]

Others

In addition to the aforementioned sexual anomalies, there are other unclassified sexual anomalies. In males, this includes severe early-onset intrauterine growth restriction, isolated hypospadias, congenital hypogonadotropic hypogonadism, hypogonadism and cryptorchidism. In females, this includes Malformation syndromes, Müllerian agenesis/hypoplasia, uterine anomalies, vaginal atresia and labial adhesions. [3]

Causes

Sexual anomalies often generate from genetic abnormalities caused by many factors, leading to different sexual development. These genetic abnormalities occur during the prenatal stage of an individual's fetal development. During this stage, genetic mutations can result from endocrine disrupters in the mother's diet or environmental factors. [16] The general causes of sexual anomalies can not be outlined due to the high variability of each individual's situations. Thus, the cause of each specific anomaly has to be studied independently.

Sexual differentiation occurs through various processes during the prenatal development period of the fetus. These processes are initiated and regulated by biological metabolites such as DNA, hormones and proteins. The initial steps of sexual differentiation begin with the development of the gonads and genitals. This process is consistent with both genders spanning over the course of the first 6 weeks following conception, during which the embryo remains pluripotent. [17] Differentiation of the gonads begins after the 6th week, which is determined by the sex-determining region Y (SRY) gene in the Y chromosome. [9]

The SRY gene plays an important role in developing the testes of a male individual. Following the development of the testes, hormones synthesized within the testes regulate the differentiation of both internal and external parts of the genitals. The absence of the testicles or the hormones synthesized may lead to irregular differentiation of the genitals. Genetic abnormalities or environmental factors that influence these procedures may lead to the incomplete development of the gonads and the genitals. These malformations can occur any time during the development or the birth of the embryo, manifesting as ambiguous genitals or dissonance within the genotypic and phenotypic sex of the individual, leading to a late onset of puberty, amenorrhea, a lack of or excess virilization, or later in life, infertility or early occurrence of menopause. [18]

Diagnosis and symptoms

First line diagnostic tests (prenatal)

Human male karyotype Human male karyotype.gif
Human male karyotype

Family history

Analysis of karyotype

  • Peripheral blood is collected for karyotyping. This helps classify the patient in one of the three main categories of DSD: chromosomal variation, gonadal development disorders and abnormal genital development. [3]

Abdominal ultrasounds

  • The presence of gonads, uterus and vagina should be monitored. This can be done through abdominal ultrasounds. However, the absence of these sex organs will lead to difficulties in gender identification. [3]

Second line diagnostic tests (postnatal)

Physical Examination

  1. Inspection of the genitalia with care and palpation must be conducted with the following points in mind. [3]
  2. Palpation of gonads from the labioscrotal fold to the abdomen (inguinal canal). [3]
  3. Hydration and blood pressure assessment should be conducted. [3]
  4. Additional dysmorphic features should be ruled out because genitalia malformations would occur if the patient has multiple malformation syndromes. [3]

Evaluation of hormones 48 hours after birth

  • 17-Hydroxyprogesterone can be used to screen for congenital adrenal hyperplasia (CAH). This is commonly found in patients with 46, XX DSD. [3] [19]
  • Dehydroepiandrosterone (DHEA) in addition to progesterone allows for the diagnosis of more uncommon forms of CAH and other inherited disorders. [3]
  • Base testosterone, follicle stimulating hormone (FSH) and luteinising hormone (LH) levels are precursors in individuals with 46,XX DSD. These tests are conducted within the timeframe of thirty hours post-birth to anywhere between fifteen and ninety days post-birth. This data collected within time frame can be used to gauge the growth of the fetus when it reaches six months of age. [3] [19]
  • Basal cortisol levels and adrenocorticotropic hormone (ACTH) is essential in diagnosing panhypopituitarism and enzymatic disorders affecting adrenal steroidogenesis. [3]
  • The anti-Müllerian hormone is used for evaluating the function of Sertoli cells. [3]
  • A urinary steroid profile shows the ratio of precursor metabolites within measured urine concentrations and the resultant products produced indicates the enzyme is the cause of a sexual defect. This is a more specific procedure in the detection of the defect in comparison to analysing blood. [3]

Treatment and management

The treatment and/or management of DSDs with atypical genitalia will vary from person to person. This may include gender affirmation surgery, medical treatment and surgical treatment.

Gender affirmation surgery

Gender affirmation plays a critical role in the management of sexual anomaly cases. Ultimately, the parents and a multidisciplinary team are responsible for assigning the sex that is affirmative the gender of the concerned person. The current guidelines of gender affirmation include the psychosocial effects in adults with etiological diagnosis, the potential for fertility, surgical opportunities and hormone replacement therapy in the course of puberty. [20] [5]

There are other factors considered during this process. This may include cultural and religious factors as well as the implications it has on the individual in later life. It is regulated by reference centers with groups specialised in managing cases of sexual anomalies. [5]

Medical treatment

Hormonal treatment is an accepted and standardised approach to treat different congenital sexual anomalies. Patients that are deficient in hormones produced by the adrenal glands require immediate medical attention. They are given a hormone called hydrocortisone, a form of hormone replacement therapy, with the objective to induce puberty. [5]

Utilizing sex steroids as hormonal therapy is deemed controversial with concerns of its duration of initiation, dosage and regimen. [5] However, it is agreed amongst most clinicians that low doses of hormonal treatment should begin around the age of 11 to 12 years old and should be increased progressively. [5]

Surgical treatment

Surgical procedures are an alternative to hormonal treatment available for patients to address genital anomalies and improve the body's sexual functions. However, a common dilemma in these procedures is that they are often derived from the patient's expectation of 'normal' genitals from an aesthetic and functional standpoint. Oftentimes, this leads to extensive surgical interventions. [21]

In most cases, surgical procedures result in permanent changes to the appearance and function of the patient's body. Therefore, the decision to proceed with this arrangement must be a joint agreement between the family and the multidisciplinary team. The most ideal situation would be to include the patient as part of the decision-making process. However, cases where surgical treatments were performed at an early age are recognised as mutilation of the body. Subsequently, it has become increasingly common to defer surgical treatments until the patient is of appropriate age to be involved in the decision-making process. [5]

Controversy and implications

Even though the term disorder of sex development (DSD) is widely accepted by the medical community, its suitability and adequacy to represent these individuals are criticised by many support and advocacy groups. Firstly, the word 'disorder' carries negative connotations. Secondly, with current nomenclature, DSD is an overly generalised term for conditions that do not have differences in genital appearance or gender identity (e.g. Klinefelter syndrome and Turner syndrome). Thirdly, the term 'DSD' lacks specificity and clarity; and therefore unhelpful in the diagnosis process. Hence, many support groups and advocates believe that the medical community should discontinue the use of 'DSD' as a designation tool. [22]

Furthermore, people who live with conditions regarding sexual abnormalities may encounter various mental and physical health problems. This may include traumatic experience with their own bodies, dissatisfaction with body image, low-self esteem, anxiety, depression, bipolar disorders, eating disorders, personality disorders, schizophrenia disorders, trauma and stress-related disorders, etc. [23]

See also

Related Research Articles

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5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in SRD5A2, a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum.

<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">Virilization</span> Biological development of male sex characteristics

Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.

<span class="mw-page-title-main">Intersex medical interventions</span> Performed to modify atypical or ambiguous genitalia

Intersex medical interventions (IMI), also known as intersex genital mutilations (IGM), are surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primarily for the purposes of making a person's appearance more typical and to reduce the likelihood of future problems. The history of intersex surgery has been characterized by controversy due to reports that surgery can compromise sexual function and sensation, and create lifelong health issues. The medical interventions can be for a variety of reasons, due to the enormous variety of the disorders of sex development. Some disorders, such as salt-wasting disorder, can be life-threatening if left untreated.

<span class="mw-page-title-main">History of intersex surgery</span>

The history of intersex surgery is intertwined with the development of the specialities of pediatric surgery, pediatric urology, and pediatric endocrinology, with our increasingly refined understanding of sexual differentiation, with the development of political advocacy groups united by a human qualified analysis, and in the last decade by doubts as to efficacy, and controversy over when and even whether some procedures should be performed.

<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">Human reproductive system</span> Organs involved in reproduction

The human reproductive system includes the male reproductive system which functions to produce and deposit sperm; and the female reproductive system which functions to produce egg cells, and to protect and nourish the fetus until birth. Humans have a high level of sexual differentiation. In addition to differences in nearly every reproductive organ, there are numerous differences in typical secondary sex characteristics.

<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">Gonadal dysgenesis</span> Congenital disorder of the reproductive system

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. 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.

<span class="mw-page-title-main">Partial androgen insensitivity syndrome</span> Medical condition

Partial androgen insensitivity syndrome (PAIS) is a condition that results in the partial inability of the cell to respond to androgens. It is an X linked recessive condition. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is clinically significant only when it occurs in individuals with a Y chromosome. Clinical features include ambiguous genitalia at birth and primary amenhorrhoea with clitoromegaly with inguinal masses. Müllerian structures are not present in the individual.

<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">Complete androgen insensitivity syndrome</span> Medical condition

Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals who are exposed to significant amounts of testosterone at some point in their lives. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does allow, without significant impairment, female genital and sexual development in those with the condition.

<span class="mw-page-title-main">Intersex</span> Atypical congenital variations of sex characteristics

Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical binary notions of male or female bodies".

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

<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 genetic males. 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.

<span class="mw-page-title-main">Quigley scale</span> Rating scale for morphology of human genitalia

The Quigley scale is a descriptive, visual system of phenotypic grading that defines seven classes between "fully masculinized" and "fully feminized" genitalia. It was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995. It is similar in function to the Prader scale and is used to describe genitalia in cases of androgen insensitivity syndrome, including complete androgen insensitivity syndrome, partial androgen insensitivity syndrome and mild androgen insensitivity syndrome.

<span class="mw-page-title-main">Definitions of intersex</span>

Various criteria have been offered for the definition of intersex, including ambiguous genitalia and atypical genitalia.

References

  1. ↑ Sreenivasan, R.; Alankarage, D.; Harley, V. (2017-01-01). "Disorders of Sex Development Loci☆". Disorders of Sex Development Loci. Elsevier. doi:10.1016/B978-0-12-809633-8.06552-3. ISBN   9780128096338.
  2. ↑ Achermann, John C.; Hughes, Ieuan A. (2016), "Pediatric Disorders of Sex Development", Williams Textbook of Endocrinology, Elsevier, pp. 893–963, doi:10.1016/b978-0-323-29738-7.00023-x, ISBN   978-0-323-29738-7 , retrieved 2021-04-01
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Guerrero-Fernández, Julio; Azcona San Julián, Cristina; Barreiro Conde, Jesús; Bermúdez de la Vega, José Antonio; Carcavilla Urquí, Atilano; Castaño González, Luis Antonio; Martos Tello, José María; Rodríguez Estévez, Amaya; Yeste Fernández, Diego; Martínez Martínez, Leopoldo; Martínez-Urrutia, María José (2018). "Management guidelines for disorders/different sex development (DSD)". Anales de Pediatría (English Edition). 89 (5): 315.e1–315.e19. doi: 10.1016/j.anpede.2018.06.006 . PMID   30033107.
  4. ↑ "Ambiguous genitalia - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2021-04-01.
  5. 1 2 3 4 5 6 7 Deligdisch-Schor, Liane; Mareş Miceli, Angelica, eds. (2020). Hormonal Pathology of the Uterus. Advances in Experimental Medicine and Biology. Vol. 1242. p. 133. doi:10.1007/978-3-030-38474-6. ISBN   978-3-030-38473-9. ISSN   0065-2598. S2CID   218624824.
  6. 1 2 Kinter, Kevin; Anekar, Aabha (2021-03-13). "Biochemistry, Dihydrotestosterone". StatPearls.
  7. ↑ Hodges, Frederick Mansfield S.; Denniston, George C.; Milos, Marilyn Fayre (2007). Male and Female Circumcision: Medical, Legal, and Ethical Considerations in Pediatric Practice. Springer US. p. 10. ISBN   978-0-58539-937-9 . Retrieved November 24, 2023.
  8. ↑ Martin, Richard J.; Fanaroff, Avory A.; Walsh, Michele C. (2014). Fanaroff and Martin's Neonatal-Perinatal Medicine E-Book: Diseases of the Fetus and Infant. Elsevier Health Sciences. p. 1522. ISBN   978-0-32329-537-6 . Retrieved November 24, 2023.
  9. 1 2 3 4 5 A, Aatsha P.; Krishan, Kewal (2020-05-30). "Embryology, Sexual Development". StatPearls.
  10. 1 2 Momodu, Ifeanyi; Lee, Brian; Singh, Gurdeep (2021-02-05). "Congenital Adrenal Hyperplasia". StatPearls.
  11. ↑ Witchel, Selma Feldman (April 2018). "Disorders of sex development". Best Practice & Research Clinical Obstetrics & Gynaecology. 48: 90–102. doi:10.1016/j.bpobgyn.2017.11.005. PMC   5866176 . PMID   29503125.
  12. 1 2 Witchel, Selma Feldman (2018). "Disorders of sex development". Best Practice & Research Clinical Obstetrics & Gynaecology. 48: 90–102. doi:10.1016/j.bpobgyn.2017.11.005. PMC   5866176 . PMID   29503125.
  13. 1 2 3 "Klinefelter syndrome - Symptoms and causes". Mayo Clinic. Retrieved 2021-04-01.
  14. ↑ Gravholt, Claus H; Andersen, Niels H; Conway, Gerard S; Dekkers, Olaf M; Geffner, Mitchell E; Klein, Karen O; Lin, Angela E; Mauras, Nelly; Quigley, Charmian A; Rubin, Karen; Sandberg, David E (2017). "Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting". European Journal of Endocrinology. 177 (3): G1–G70. doi: 10.1530/EJE-17-0430 . ISSN   0804-4643. PMID   28705803.
  15. ↑ Wolffenbuttel, K. P.; Hersmus, R.; Stoop, H.; Biermann, K.; Hoebeke, P.; Cools, M.; Looijenga, L. H. J. (2016-12-12). "Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management". Journal of Pediatric Urology. 12 (6): 411–416. doi:10.1016/j.jpurol.2016.08.015. ISSN   1873-4898. PMID   27769830.
  16. ↑ Rogers, Kara (2016-12-05). "Endocrine disruptor | biochemistry". Encyclopedia Britannica. Retrieved 2021-04-13.
  17. ↑ Peinkofer, Gabriel; Burkert, Karsten; Urban, Katja; Krausgrill, Benjamin; Hescheler, Jürgen; Saric, Tomo; Halbach, Marcel (2016). "From Early Embryonic to Adult Stage: Comparative Study of Action Potentials of Native and Pluripotent Stem Cell-Derived Cardiomyocytes". Stem Cells and Development. 25 (19): 1397–1406. doi:10.1089/scd.2016.0073. ISSN   1547-3287. PMID   27484788.
  18. ↑ Pal, AsokeK; Ambulkar, PrafullaS; Sontakke, BharatR; Talhar, ShwetaS; Bokariya, Pradeep; Gujar, VijayK (2019). "A study on chromosomal analysis of patients with primary amenorrhea". Journal of Human Reproductive Sciences. 12 (1): 29–34. doi: 10.4103/jhrs.JHRS_125_17 . ISSN   0974-1208. PMC   6472206 . PMID   31007464.
  19. 1 2 Juniarto, A. Zulfa; van der Zwan, Yvonne G.; Santosa, Ardy; Ariani, Mahayu Dewi; Eggers, Stefanie; Hersmus, Remko; Themmen, Axel P.N.; Bruggenwirth, Hennie T.; Wolffenbuttel, Katja P.; Sinclair, Andrew; White, Stefan J. (2016). "Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia". Clinical Endocrinology. 85 (2): 247–257. doi:10.1111/cen.13051. hdl: 11343/291143 . PMID   26935236. S2CID   20604226.
  20. ↑ Mareş Miceli, Angelica (2020), Deligdisch-Schor, Liane; Mareş Miceli, Angelica (eds.), "Replacement Hormone Therapy for Gender Dysphoria and Congenital Sexual Anomalies", Hormonal Pathology of the Uterus, Advances in Experimental Medicine and Biology, vol. 1242, Cham: Springer International Publishing, pp. 121–143, doi:10.1007/978-3-030-38474-6_7, ISBN   978-3-030-38474-6, PMID   32406031 , retrieved 2023-10-11
  21. ↑ "Klinefelter Syndrome". Physiopedia. 2020-10-22. Retrieved 2021-04-11.
  22. ↑ Houk, Christopher P; Baskin, Laurence S; Levitsky, Lynne L (Jan 9, 2021). Geffner, Mitchell E; Hoppin, Alison G (eds.). "Management of the infant with atypical genitalia (disorder of sex development)". UpToDate. Retrieved April 9, 2021.
  23. ↑ "Supporting yourself - Intersex people". headtohealth.gov.au. 2019-09-24. Retrieved 2021-04-01.
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