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Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and include: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent. Some content on this current page requires updating to reflect the new terminology. Some abnormalities relate to gonad development and their function, which can then impact later on sexual development. Other abnormalities are related to the tract and external genitalia, which can also stem from a gonadal abnormality. |
Congenital adrenal hyperplasia, an impairment of cortisol production by the adrenal cortex, is one of the most common causes of intersex genitalia at birth (More? Adrenal Abnormalities). Genetically male (XY) infants born with undervirilized genitalia (androgen insensitivity syndrome, cloacal exstrophy) are generally assigned and reared as girls.
Page Links: Introduction | Some Recent Findings | Disorders of Sex Development | Chromosomal | Gonadal Dysfunction | Spermatogenesis | Leydig Cell Hypoplasia | Polycystic Ovary Syndrome | Tract Abnormalities | Gonadal Descent | External Genitalia | Epoophoron | Hypospadias | References | WWWLinks | Glossary
Related Pages: Spermatogenesis Abnormalities | Adrenal Abnormalities
Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006 Aug;118(2):e488-500. PMID: 16882788 | Pediatrics Link
Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjöld A, Ekbom A, Melbye M. Maternal and gestational risk factors for hypospadias. Environ Health Perspect. 2008 Aug;116(8):1071-6. (More? Hypospadias)
"study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. ...A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias"
Porter MB. Polycystic ovary syndrome: the controversy of diagnosis by ultrasound. Semin Reprod Med. 2008 May;26(3):241-51.
"These criteria were revised in 2003 at the Rotterdam European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine consensus workshop to include ultrasound polycystic ovarian morphology (PCOM) as one of the two of three criteria (chronic anovulation and clinical/or biochemical signs of hyperandrogenism) necessary for establishing the diagnosis of PCOS.....The inclusion of PCOM sparked a controversy as it broadens the population of women who meet the criteria for PCOS and allows for the creation of two phenotypically different patient populations who previously would have been excluded." (More? Polycystic Ovary Syndrome)
Kossack N, Simoni M, Richter-Unruh A, Themmen AP, Gromoll J. Mutations in a Novel, Cryptic Exon of the Luteinizing Hormone/Chorionic Gonadotropin Receptor Gene Cause Male Pseudohermaphroditism. PLoS Med. 2008 Apr 22;5(4):e88
"LHCGR gene is apparently normal in 50% of people with Leydig cell hypoplasia (LCH; also called male pseudohermaphroditism) intersex condition. ...novel exon identified as a new regulatory element within the genomic organization of LHCGR" (More? Hermaphroditism)
Ferlin A, Zuccarello D, Garolla A, Selice R, Foresta C. Hormonal and genetic control of testicular descent. Reprod Biomed Online. 2007 Dec;15(6):659-65. Review
"Major actors of testicular descent are the Leydig cell-derived hormones testosterone and insulin-like factor 3, even if other factors may play a role. ...Mutations in the gene for insulin-like factor 3 and its receptor and in the androgen receptor gene explain a minority of cases of cryptorchidism" (More? Gonadal Descent)
Baskin LS, Ebbers MB. Hypospadias: anatomy, etiology, and technique. J Pediatr Surg. 2006 Mar;41(3):463-72.
"Hypospadias is one of the most common congenital anomalies defined by abortive development of the urethral spongiosum, the ventral prepuce and in more severe cases penile chordee. The etiology of hypospadias remains unknown with environmental exposure in the form of endocrine disruptors the most likely explanation for the worldwide increase in incidence in the last three decades. ...This article reviews the pertinent embryology, anatomy and the most common hypospadias reconstructive operations to accomplish a successful repair." (More? Hypospadias)
The previous human sex development terminology (true hermaphrodites, male pseudohermaphrodites and female pseudohermaphrodites) are considered outdated and stigmatising and have been replaced with the general term Disorders of Sex Development (DSD) established by the Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006 Aug;118(2):e488-500. PMID: 16882788 | Pediatrics Link
Previous Terminology |
New Proposed Terminology |
Intersex |
DSD |
Male pseudohermaphrodite, undervirilization of an XY male, and undermasculinization of an XY male |
46,XY DSD |
Female pseudohermaphrodite, overvirilization of an XX female, and masculinization of an XX female |
46,XX DSD |
True hermaphrodite |
Ovotesticular DSD |
XX male or XX sex reversal |
46,XX testicular DSD |
XY sex reversal |
46,XY complete gonadal dysgenesis |
Clinically, delaying sex-assignment surgery can result in an increased risk of gonadal malignancy (More? eMJA Jun09 Editorial).
Links: DSD Guidelines | Handbook for Parents | Pediatrics Link | eMJA Jun09 Editorial |
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45,X (Turner syndrome and variants) Monosomy XO, 99% non-viable embryos, fail to sexually mature at puberty. Named after Henry Turner (1938), an American clinician who first described the condition. |
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47,XXY (Klinefelter syndrome and variants) 47, XXY Affects approximately one in every 660 men who begin normal male and become infertile. Features: tall, mental dullness, narrow shoulders, broad hips, sparse body hair, gynecomastia, small testicles, androgen deficiency, azoospermia, behaviour problems and decreased verbal intelligence. |
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Another form of Klinefelter syndrome showing the 49, YXXXX form. |
Males 46, XX, Develop as male, infertile adults, portion of SRY gene located on one X.
Search PubMed: term= Turner's Syndrome (Jun06: 5930 Articles 541 Reviews) | Klinefelter's Syndrome (Jun06: 3080 Articles 297 Reviews) |
Review - Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007 Apr;4(4):192-204.
Gonads fail to develop properly. Alterations of the SRY gene (by point mutation or deletions) can lead to a gonadal dysgenesis (XY female) also called Swyer's syndrome.
Gonadal Dysgenesis: 46,XX, Swyer's syndrome
Mixed Gonadal Dysgenesis: 45,X/46,XY
Primary Hypogonadism: 46,XX, affected females
Primary Hypogonadism: Defective anterior pituitary production of gonadotropin, lack of gonadotropin-releasing hormone
(see also Polycystic Ovary Syndrome below)
Search PubMed: term= Swyer's syndrome (Jun06: 24 Articles 2 Reviews) | Primary Hypogonadism (Jun06: 8406 Articles 1018 Reviews)
Links: Week 1 Male Sex Determination (sry) | OMIM - GONADAL DYSGENESIS, XY FEMALE TYPE | Androgen Insensitivity Syndrome Support Group (AISSG)
These are male abnormalities that generally become apparent late postnatally after puberty or when reproduction is planned. These condations would not be detected (unless with a genetic history) in prenatal and early postnatal development.
Oligospermia (Low Sperm Count) - Less than 20 million sperm after 72 hour abstinence from sex
| Azoospermia (Absent Sperm) | |
Two main forms identified as:
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Okada H, Tajima A, Shichiri K, Tanaka A, Tanaka K, Inoue I. Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility. PLoS Genet. 2008 Feb;4(2):e26. |
Human Seminiferious Tubule - Non-obstructive azoospermia and Obstructive azoospermia (Image: Okada, etal, 2008) |
Immotile Cilia Syndrome
A disorder of sperm motility which can lead to infertility.
Globozoospermia (round-headed spermatozoa)
Acrosome malformation of spermatids (More? Acrosome Malformation)
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Leydig cell hypoplasia, (LCH) is an autosomal recessive disorder in individuals with a 46,XY karyotype who have a predominantly female phenotype (blind-ending vagina, absence of breast development, primary amenorrhea, presence of testicular structures) that is with gonads of one sex, external genitalia of opposite. One cause has been recently identified as the presence of a cryptic exon in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene (More? Kossack N, etal., 2008) |
Normal spermatogenesis, Leydig cells are positive for LHCGR. |
(Image: modified from PLOS - Kossack N, etal., 2008, Bar indicates 100 μM) |
Supernumerary ovaries are rare occurances (1:29,000-700,000) where a third ovary is entirely separated from the normal (eutopic) ovary and may be located in a range of sites including: the omentum, retroperitoneally or intrarenal (extremely rare). There additional ovaries have also been associated with, and detected by, tumors which can arise in the ectopic ovarian tissue.
Search PubMed: term = Supernumerary Ovary
Polycystic ovary syndrome (PCOS) or Stein–Leventhal syndrome (1930s researchers) is a metabolic syndrome with many other symptoms, ovarian cysts arise through incomplete follicular development or failure of ovulation. The two hormones insulin and testosterone are generally abnormal, leading to ovulation problems.
Links: Pedlineplus - Polycystic Ovary Syndrome | Pedlineplus - ovarian cysts | OMIM- Polycystic Ovary Syndrome | NCBI Bookshelf - Endocrinology
References:
Review - Norman RJ, Wu R, Stankiewicz MT. Polycystic ovary syndrome. Med J Aust. 2004 Feb 2;180(3):132-7.
Porter MB. Polycystic ovary syndrome: the controversy of diagnosis by ultrasound. Semin Reprod Med. 2008 May;26(3):241-51.
Clinical Trial - Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ Link |
Search PubMed: term = Polycystic ovary syndrome (Jun06: 6438 Articles 1154 Reviews)
Epoophoron (broad ligament cyst) is an ovary abnormality occuring when a segment of the mesonephric duct remains in the female, associated with either the ovary and broad ligament. This "male remnant" will appear as a cyst (broad ligament cyst, adnexal papillary cystadenoma of probable mesonephric origin, APMO) with an appearance that differs depending upon the state of differentiation when the original abnormality occurred. |
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Many different forms
Uterine: associated with other anomolies, unicornuate uterus
Vagina: agenesis, atresia (More? Endocrine Abnormalities)
Ductus Deferens: Unilateral or bilateral absence, failure of mesonephric duct to differentiate
Due to the relative positions of the male (external) and female (internal) gonads and the pathways for their movement, failure of gonad descent is more apparent and common in male cryptorchidism than female undescended ovaries.
Cryptorchidism is an abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males. Descent may complete postnatally in the first year, failure to descend can result in sterility. Testis descent is thought to have 2 phases:
Polymorphisms in the estrogen receptor alpha (ESR1) gene have been found to not associate with occurrence, but do associate with the severity of cryptorchidism. (PMID: 18452179) |
Typical sites of gonad location in true and ectopic cryptorchidism |
Search PubMed: term= Cryptorchidism (Jun06: 6821 Articles 631 Reviews)
Links: AAFP - The Undescended Testicle | Amann RP, Veeramachaneni DN. Cryptorchidism in common eutherian mammals. Reproduction. 2007 Mar;133(3):541-61.
Undescended Ovaries is a reasonably rare gonad abnormality, often detected following clinical assessment of fertility problems and may also be associated with other uterine malformations (unicornuate uterus).
Can be detected by abdominal ultrasound or by combination of mild clomiphene citrate (CC) stimulation with magnetic resonance imaging (MRI). (More? ultrasound | magnetic resonance imaging | clomiphene citrate)
References:
Dietrich JE, Hertweck SP, Bond S. Undescended ovaries: a clinical review. J Pediatr Adolesc Gynecol. 2007 Apr;20(2):57-60.
Search PubMed: term= Undescended Ovaries (Jun08: 27 Articles)
Male Hydrocele is a fluid-filled cavity of either testis or spermatic cord, where peritoneal fluid passes into a patent processus vaginalis.
Female Hydrocele is a similar, but rarer, fluid-filled cavity occuring in the female as a pouch of peritoneum extending into the labium majorum (canal of Nuck).
Search PubMed: term= Hydrocele (Jun06: 1797 Articles 151 Reviews) | canal of Nuck
Germ cell tumors of the testis are the most frequent testicular neoplasms with rarer stromal tumours (gonadoblastoma).
Gonadoblastoma is a rare stromal tumour formed by non-germ cells (Sertoli cells, cells of Leydig, granulosa cells) in the gonad (testis).
There is also an increased risk for gonadoblastoma in females (phenotypic) with dysgenetic gonads and some Y-chromosomal material.
Markers for germ cell tumors - beta HCG and alpha-fetoprotein
Sacrococcygeal type I extragonadal germ cell tumor, germ cells are located outside the gonad in neonates and infants.
Links: OMIM- Gonadoblastoma
Search PubMed: term= Gonadoblastoma (Jun06: 478 Articles 34 Reviews) gonadoblastoma locus on the Y chromosome (GBY).
The most common external genitalia birth abnormality is male hypospadia, suggested in some publications to occur as frequently as 1 in every 125 live male birth.
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Hypospadias most common penis abnormality (1 in 300) from a failure of male urogenital folds to fuse in various regions and resulting in a proximally displaced urethral meatus. The cause is unknown, but suggested to involve many factors either indivdually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals. Infants with hypospadias should not undergo circumcision. hypospadia classification | hypospadia repair Opening of the urethra (meatus) on the inferior surface (ring) not at the tip. Other regions where urethra may open to the surface (dashed line). Hypospadias is classified by the location of the opening (More? hypospadias classification) |
Classification of Hypospadias
Hypospadia is classified by the location of the opening (meatus).
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A Anterior - on inferior surface of glans penis.
(Image: Baskin LS, Himes K, Colborn T., 2001) |
Surgical Repair
Depending on the class of hypospadias there are a number of different surgical repair techniques including: orthoplasty or penile straightening, urethroplasty, meatoplasty and glanuloplasty, scrotoplasty and skin coverage.
References:
Baskin LS, Ebbers MB. Hypospadias: anatomy, etiology, and technique. J Pediatr Surg. 2006 Mar;41(3):463-72.
Baskin LS, Himes K, Colborn T. Hypospadias and endocrine disruption: is there a connection? Environ Health Perspect. 2001 Nov;109(11):1175-83. (EPH Link)
Search PubMed: term= Hypospadias (Jun06: 3776 Articles 281 Reviews)
Links: Medline Plus - Hypospadias | Medline Plus - Hypospadias repair | Medline Plus - Penis Disorders |
Links: Journals | Online Textbooks | Search Textbooks | Reviews | Articles | Search PubMed | Glossary
Search PubMed: Disorders of Sex Development | Hypospadia | Undescended ovaries |
A list of results from a search for "gonad" of the OMIM Database below which are shown some specific abnormalities. OMIM Database Entries List- Gonad
Undescended Testis - 219050 CRYPTORCHIDISM
Use the alphabetical list below to find definitions of terms that are new to you or use the Google search window to search UNSW Embryology site.
A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Old Glossary |
congenital adrenal hyperplasia - (CAH, adrenal virilism) Abnormality of the fetal adrenal cortex, alters cortisol and androgens with different effects dependent upon sex: in females masculization of the external genitalia; in males, disorder often unnoticed until postnatally. In both sexes, accelerated skeletal growth and sexual maturation is seen in late childhood. Caused by a deficiency or absence of the enzyme 21-hydroxylase in the adrenal cortex. (More? Endocrine Adrenal - congenital adrenal hyperplasia)
Disorder of Sex Development - (DSD) A new terminology to describe disorders of sex development. The previous human sex development terminology (intersex, true hermaphrodites, male pseudohermaphrodites and female pseudohermaphrodites) are considered outdated and stigmatising and have been replaced with the general term Disorders of Sex Development (DSD) established by the Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006 Aug;118(2):e488-500. PMID: 16882788 | Pediatrics Link
partial androgen insensitivity - A genetic disorder causing ambiguous genitalia in 46,XY individuals. This X-linked disease is due to an absence or deficiency of androgen receptors in the androgen target tissues (genital skin area).
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This page introduces a few specific examples of abnormalities of the reproductive system. Content on this page updated to reflect the new terminology for Disorders of Sex Development, based upon the 2006 Consensus Statement on Management of Intersex Disorders.
The male and female reproductive systems develop initially "indifferently", it is the product of the Y chromosome SRY gene that makes the difference.
This complex pattern of genetic regulation, differentiation and the long over which this occurs, leads to many abnormalities associated with gonad, internal and external genital development.
The previous terminology that may exist in historic literature (intersex, pseudohermaphroditism, hermaphroditism and sex reversal) should now be replaced with the term "disorders of sex development” (DSD), as defined by congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.
Please email Dr Mark Hill if you wish to make a comment about this current project.
