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 will determine how the developing bipotent gonads differentiate (e.g., into a testis or an ovary).
- The developing gonads will then secrete hormones:
- The presence and/or absence of specific hormones will determine how the remaining structures differentiate.
- In general, female organs and structures are the “default” phenotype if specific genes and hormones 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
- Testes:
- Wolffian structures differentiate from the Wolffian (mesonephric) ducts in the presence of testosterone:
- Epididymis
- Vas deferens
- Seminal vesicles
- Ejaculatory ducts
- Müllerian structures differentiate from the Müllerian (paramesonephric) ducts when AMH is absent:
- Uterus
- Fallopian tubes
- Upper ⅓ of the vagina
- External genitalia develop from the undifferentiated genital tubercle, genital swelling, and genital folds based on the presence or absence of testosterone.
- Male: testosterone → penis and scrotum
- Female: lack of testosterone → clitoris, labia majora, labia minora
- Secondary sexual characteristics develop based on the hormonal milieu at 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
- Testes secrete:
- AMH
- Testosterone
- DHT
- The above hormones 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 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 and AMH are absent.
- Embryos develop in the “female hormonal environment” within their mother; thus, it is unclear whether hormones produced by the fetus are required for their development.
Summary of Common Disorders of Sexual Development
| Disorder | Pathophysiology | Key points |
|---|---|---|
| Androgen insensitivity syndrome (AIS) |
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| 5-α-reductase deficiency |
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| Aromatase deficiency |
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| Congenital adrenal hyperplasia |
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| Kallmann syndrome |
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| 46,XX gonadal dysgenesis |
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| Swyer syndrome |
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| True hermaphroditism |
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| Turner syndrome |
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| 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 visible?
- Is the uterus 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).
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. On exam, well-developed breasts and absence of pubic hair are noted, indicating exposure to estrogen without significant testosterone exposure.
Characteristic features of a female with 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 and 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
- Assessment of the gonads
Consider imaging of the kidneys and 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
