Overview of Sex Development
Definition
Disorders of sexual development are a group of conditions characterized by atypical sexual development in an individual, involving abnormalities in the structure and/or function of both the internal reproductive organs and/or external genitalia.
Overview of typical sex development
- Chromosomal sex → determines gonadal sex → determines phenotypic sex
- Up until 6 weeks of gestation, sex development is identical and nonbinary. The developing structures include:
- Nonbinary, bipotent, undifferentiated gonads
- Wolffian and Müllerian ducts (both are present in both sexes initially)
- Urogenital sinus
- The genital tubercle, genital swellings, and genital folds
- The genes present at fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week will determine how the developing bipotent gonads differentiate (e.g., into a testis or an ovary).
- The developing gonads will then secrete
hormones
Hormones
Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments.
Hormones: Overview:
- The presence and/or absence of specific hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview will determine how the remaining structures differentiate.
- In general, female organs and structures are the “default” phenotype if specific genes and hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview are not present to stimulate male differentiation.
Sex organs and characteristics
- Gonads develop based on the karyotype/genes that are present.
- Testes:
- Develop when sex-determining region of the Y chromosome (SRY gene) is present
- Secrete testosterone and anti-Müllerian hormone (AMH)
- Ovaries develop when the X chromosome is present and/or the SRY is absent.
- Ovotestis: a gonad containing both ovarian and testicular tissue found in patients with true hermaphroditism True hermaphroditism True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. True Hermaphroditism
- Testes:
- Wolffian structures differentiate from the Wolffian (mesonephric) ducts in the presence of testosterone:
- Epididymis
- Vas deferens
- Seminal vesicles Seminal vesicles A saclike, glandular diverticulum on each ductus deferens in male vertebrates. It is united with the excretory duct and serves for temporary storage of semen. Prostate and other Male Reproductive Glands
- Ejaculatory ducts
- Müllerian structures differentiate from the Müllerian (paramesonephric) ducts when AMH is absent:
- Uterus
- Fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall
- Upper ⅓ of the vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
- External genitalia develop from the undifferentiated genital tubercle, genital swelling, and genital folds based on the presence or absence of testosterone.
- Male: testosterone → penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis and scrotum
- Female: lack of testosterone → clitoris, labia majora, labia minora
- Secondary sexual characteristics develop based on the hormonal milieu at
puberty
Puberty
Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems.
Puberty.
- Androgenic characteristics: due to the presence of testosterone and/or dihydrotestosterone (DHT)
- Pubic and axillary hair
- Facial and body hair in an androgenic distribution and quality (dark and coarse)
- Deepening of the voice
- ↑ Muscle mass
- Estrogenic characteristics result from the presence of estrogen:
- Breast development
- Wider hips
- Androgenic characteristics: due to the presence of testosterone and/or dihydrotestosterone (DHT)
Sex differentiation
Image by Lecturio.
Phenotypic differentiation of the external genitalia in male and female embryos
Image by Lecturio.
Typical male development
Male development begins due to the presence of the sex-determining region of the Y chromosome gene (SRY gene).
- SRY gene → produces SRY protein (also known as testis-determining factor):
- Stimulates the differentiation of the bipotent gonad into testes
- Stimulates development of:
- Seminiferous tubules
- Leydig cells
- Sertoli cells
- Suppresses the differentiation of ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
- Testes secrete:
- AMH
- Testosterone
- DHT
- The above
hormones
Hormones
Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments.
Hormones: Overview cause:
- Stimulation of the Wolffian ducts (around the 8th week) to differentiate into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts
- Regression of the Müllerian ducts
- Differentiation of the prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands and external genitalia
- The process of differentiation is largely completed by 12 weeks of gestation.
Male development
DHT: dihydrotestosteroneImage by Lecturio.
Typical female development
- Development of the ovary from the bipotent gonad requires:
- Absence of the SRY (preventing differentiation into testes)
- Presence of several genes found on chromosome 1, including:
- WNT4
- R spondin 1 (Rspo1)
- Begins around 10 weeks of development
- Differentiation and development of the Müllerian ducts and external genitalia occur when testicular androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and AMH are absent.
- Embryos develop in the “female hormonal environment” within their mother; thus, it is unclear whether hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview produced by the fetus are required for their development.
Summary of Common Disorders of Sexual Development
| Disorder | Pathophysiology | Key points |
|---|---|---|
| Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome (AIS) |
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| 5-α-reductase deficiency |
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| Aromatase deficiency Aromatase deficiency Aromatase deficiency is a very rare genetic condition with autosomal recessive inheritance. Aromatase deficiency is characterized by congenital estrogen deprivation with increased levels of testosterone due to decreased levels of the aromatase enzyme. Aromatase Deficiency |
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| Congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia |
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| Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome |
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| 46,XX gonadal dysgenesis 46,XX Gonadal Dysgenesis 46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads with no functional ovarian tissue. It is also called "pure gonadal dysgenesis" to differentiate these patients from those who present with the phenotype of Turner's syndrome. 46,XX Gonadal Dysgenesis |
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| Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome |
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| True hermaphroditism |
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| Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome |
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| Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome |
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21-hydroxylase deficiency:
Diagram of the pathophysiology of congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Principles of Diagnosis
The differential diagnosis for disorders of sexual development typically includes many of the conditions listed above. The general diagnostic approach to help determine the appropriate diagnosis is listed below.
Exam
- Genital examination:
- Ambiguous genitalia is likely due to ↑ testosterone/DHT in individuals without SRY (e.g., 46,XX) or ↓ testosterone in individuals with SRY (e.g., 46,XY)
- Assess the size and descent of testes.
- Internal pelvic examination on phenotypic females:
- Is a cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Posterior Abdominal Wall visible?
- Is the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall palpable?
- Assessment of secondary sex characteristics in adolescents/adults:
- Breast development = estrogen present
- Pubic and axillary hair = testosterone present
- Facial/body hair, deepening of the voice = testosterone present
- Look for findings associated with specific syndromes (e.g., webbed neck in Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome).
Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome:
Image: “Complete androgen insensitivity syndrome or testicular feminization: Review of literature based on a case report” by The Pan African Medical Journal. License: CC BY 2.0
A 30-year-old patient with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea. On exam, well-developed breasts Breasts The breasts are found on the anterior thoracic wall and consist of mammary glands surrounded by connective tissue. The mammary glands are modified apocrine sweat glands that produce milk, which serves as nutrition for infants. Breasts are rudimentary and usually nonfunctioning in men. Breasts and absence of pubic hair are noted, indicating exposure to estrogen without significant testosterone exposure.
Characteristic features of a female with Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome
Image by Lecturio.
Laboratory
- Karyotype with FISH to assess the presence or absences of the SRY gene
- Testosterone:
- Decreases in Kallman, Swyer, and Klinefelter syndromes
- Increases or is normal in androgen insensitivity syndrome (AIS), 5α-reductase deficiency, aromatase deficiency, and congenital adrenal hyperplasia
- DHT:
- Decreases with 5α-reductase deficiency
- Increases in AIS
- Follicle stimulating hormone (FSH) and luteinizing hormone (LH):
- Decrease in Kallman syndrome (due to ↓ gonadotropin-releasing hormone (GnRH))
- Increase in 46,XX gonadal dysgenesis 46,XX Gonadal Dysgenesis 46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads with no functional ovarian tissue. It is also called "pure gonadal dysgenesis" to differentiate these patients from those who present with the phenotype of Turner's syndrome. 46,XX Gonadal Dysgenesis and Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome (normal GnRH function with non-responsive gonads)
- 17-Hydroxyprogesterone: ↑ in congenital adrenal hyperplasia
Imaging
Abdominal pelvic ultrasound to assess the internal organs:
- Presence or absence of a uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall
- Assessment of the gonads
Consider imaging of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract, as abnormalities in the reproductive organs are frequently associated with renal/urinary anomalies.
Principles of Management
- Factors affecting management:
- Age of presentation (infant, adolescent, versus adult)
- Gender identity and preferences of the patient
- Hormone status
- Psychotherapy/counseling: All patients (and potentially family members) should be referred for therapy.
- Hormone replacement therapy (HRT) may be indicated in patients with hormonal deficiencies (e.g., testosterone and/or estrogen).
- Surgery:
- Abnormal gonads, especially gonadoblastomas and dysgerminomas, pose a high risk for malignancy → surgical excision recommended
- Reconstructive or reassignment surgery
References
- Patel, N., Zafar Gondal, A. (2020). Embryology, Mullerian-inhibiting Factor. StatPearls. Retrieved May 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544351/
- Chan, Y., Levitsky, L.L. (2020). Causes of differences of sex development. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/causes-of-differences-of-sex-development?source=history_widget
- Hiort, O. (2020). Typical sex development. UpToDate. Retrieved May 13, 2021, from https://www.uptodate.com/contents/typical-sex-development?source=history_widget#H1048687515
- Chan, Y., Levitsky, L.L. (2020). Evaluation of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/evaluation-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
- Houk, C.P., Baskin, L.S., Levitsky, L.L. (2020). Management of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/management-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
- Nieman, L.K. (2020). Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2021, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
- Merke, D.P., Auchus, R.J. (2020). Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency-in-infants-and-children
- Medline Plus. (2020). Swyer syndrome. Retrieved January 21, 2021, from https://medlineplus.gov/genetics/condition/swyer-syndrome/
- Ostrer, H. (2019). Swyer syndrome. National Organization for Rare Disorders. Retrieved January 21, 2021, from https://rarediseases.org/rare-diseases/swyer-syndrome/
- Moshiri, M., Chapman, T., Fechner, P.Y., et al. (2012). Evaluation and management of disorders of sex development: Multidisciplinary approach to a complex diagnosis. RadioGraphics. 32(6),1599–1618. https://pubmed.ncbi.nlm.nih.gov/23065160/
- Hiort, O., Bohring, A. (2011). 46, XX gonadal dysgenesis. Orphanet. Retrieved January 22, 2021, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=243&lng=EN
