Talk:Genital System - Abnormalities

From Embryology
About Discussion Pages  
Mark Hill.jpg
On this website the Discussion Tab or "talk pages" for a topic has been used for several purposes:
  1. References - recent and historic that relates to the topic
  2. Additional topic information - currently prepared in draft format
  3. Links - to related webpages
  4. Topic page - an edit history as used on other Wiki sites
  5. Lecture/Practical - student feedback
  6. Student Projects - online project discussions.
Links: Pubmed Most Recent | Reference Tutorial | Journal Searches

Contents

Glossary Links

Glossary: 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 | Symbols | Term Link

Cite this page: Hill, M.A. (2019, December 8) Embryology Genital System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Genital_System_-_Abnormalities

http://bestpractice.bmj.com/best-practice/monograph/1104/basics.html

2019

ICD-10 Deleted

Mark Hill (talk) 14:42, 25 March 2019 (AEDT) Removed previous ICD-10 information from page.

ICD 10 - XVII Congenital Malformations

The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Version ICD-11 coding is currently being introduced to replace ICD-10.

 ICD-11
Female genital organs
  • XA78U5 Vulva
  • XA1LK7 Vagina
  • XA99N3 Uterus
  • XA1QK0 Ovary
  • XA90F8 Placenta
  • XA7E69 Uterine adnexa
  • XA3EF0 Fallopian Tube
Male genital organs
  • XA7QV2 Penis
  • XA63E5 Prostate gland
  • XA4947 Testis
  • XA97R9 Other and unspecified male genital organs
XA12C1 Breast
  • XA5MC5 Nipple
  • XA85A1 Lactiferous duct
  • XA0US1 Central portion of breast
  • XA3LS6 Upper inner quadrant of breast
  • XA0VX8 Lower inner quadrant of breast
  • XA2Q54 Upper outer quadrant of breast
  • XA94U2 Lower outer quadrant of breast
  • XA3PG5 Axillary tail of breast
ICD-10  
Within the ICD10 classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).
ICD10 Congenital malformations of genital organs (Q50-Q56) 
The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. Includes this section on XVII Congenital Malformations.
Congenital malformations of genital organs (Q50-Q56)

Excl.: androgen resistance syndrome (E34.5) syndromes associated with anomalies in the number and form of chromosomes (90-99) testicular feminization syndrome (E34.5)

Q50 Congenital malformations of ovaries, fallopian tubes and broad ligaments
  • Q50.0 Congenital absence of ovary Excl.: Turner's syndrome (96.-)
  • Q50.1 Developmental ovarian cyst
  • Q50.2 Congenital torsion of ovary
  • Q50.3 Other congenital malformations of ovary Accessory ovary Congenital malformation of ovary NOS Ovarian streak
  • Q50.4 Embryonic cyst of fallopian tube Fimbrial cyst
  • Q50.5 Embryonic cyst of broad ligament Cyst: epoophoron Gartner's duct parovarian
  • Q50.6 Other congenital malformations of fallopian tube and broad ligament Absence Accessory Atresia (of) fallopian tube or broad ligament Congenital malformation of fallopian tube or broad ligament NOS
Q51 Congenital malformations of uterus and cervix
  • Q51.0 Agenesis and aplasia of uterus Congenital absence of uterus
  • Q51.1 Doubling of uterus with doubling of cervix and vagina
  • Q51.2 Other doubling of uterus Doubling of uterus NOS
  • Q51.3 Bicornate uterus
  • Q51.4 Unicornate uterus
  • Q51.5 Agenesis and aplasia of cervix Congenital absence of cervix
  • Q51.6 Embryonic cyst of cervix
  • Q51.7 Congenital fistulae between uterus and digestive and urinary tracts
  • Q51.8 Other congenital malformations of uterus and cervix Hypoplasia of uterus and cervix
  • Q51.9 Congenital malformation of uterus and cervix, unspecified
Q52 Other congenital malformations of female genitalia
  • Q52.0 Congenital absence of vagina
  • Q52.1 Doubling of vagina Septate vagina Excl.: doubling of vagina with doubling of uterus and cervix (51.1)
  • Q52.2 Congenital rectovaginal fistula Excl.: cloaca (43.7)
  • Q52.3 Imperforate hymen
  • Q52.4 Other congenital malformations of vagina Congenital malformation of vagina NOS Cyst: canal of Nuck, congenital embryonic vaginal
  • Q52.5 Fusion of labia
  • Q52.6 Congenital malformation of clitoris
  • Q52.7 Other congenital malformations of vulva Congenital: absence cyst malformation NOS of vulva
  • Q52.8 Other specified congenital malformations of female genitalia
  • Q52.9 Congenital malformation of female genitalia, unspecified
Q53 Undescended testicle
  • Q53.0 Ectopic testis Unilateral or bilateral ectopic testes
  • Q53.1 Undescended testicle, unilateral
  • Q53.2 Undescended testicle, bilateral
  • Q53.9 Undescended testicle, unspecified Cryptorchism NOS
Q54 Hypospadias

Excl.: epispadias (64.0)

  • Q54.0 Hypospadias, balanic Hypospadias: coronal glandular
  • Q54.1 Hypospadias, penile
  • Q54.2 Hypospadias, penoscrotal
  • Q54.3 Hypospadias, perineal
  • Q54.4 Congenital chordee
  • Q54.8 Other hypospadias
  • Q54.9 Hypospadias, unspecified
Q55 Other congenital malformations of male genital organs

Excl.: congenital hydrocele (P83.5) hypospadias (54.-)

  • Q55.0 Absence and aplasia of testis Monorchism
  • Q55.1 Hypoplasia of testis and scrotum Fusion of testes
  • Q55.2 Other congenital malformations of testis and scrotum Congenital malformation of testis or scrotum NOS Polyorchism Retractile testis Testis migrans
  • Q55.3 Atresia of vas deferens
  • Q55.4 Other congenital malformations of vas deferens, epididymis, seminal vesicles and prostate Absence or aplasia of: prostate spermatic cord Congenital malformation of vas deferens, epididymis, seminal vesicles or prostate NOS
  • Q55.5 Congenital absence and aplasia of penis
  • Q55.6 Other congenital malformations of penis Congenital malformation of penis NOS Curvature of penis (lateral) Hypoplasia of penis
  • Q55.8 Other specified congenital malformations of male genital organs
  • Q55.9 Congenital malformation of male genital organ, unspecified Congenital: anomaly deformity NOS of male genital organ
Q56 Indeterminate sex and pseudohermaphroditism

Excl.: pseudohermaphroditism: female, with adrenocortical disorder (E25.-) male, with androgen resistance (E34.5) with specified chromosomal anomaly (96-99)

  • Q56.0 Hermaphroditism, not elsewhere classified Ovotestis
  • Q56.1 Male pseudohermaphroditism, not elsewhere classified Male pseudohermaphroditism NOS
  • Q56.2 Female pseudohermaphroditism, not elsewhere classified Female pseudohermaphroditism NOS
  • Q56.3 Pseudohermaphroditism, unspecified
  • Q56.4 Indeterminate sex, unspecified Ambiguous genitalia
Please note that this category uses old terminology, that has been replaced elsewhere with "Disorders of Sex Development (DSD)".
World Health Organisation. International Statistical Classification of Diseases and Related Health Problems. (1992) 10th Revision (ICD-10). Geneva: WHO ICD-10 - 2016 Online (English)
Genital Links: genital | Lecture - Medicine | Lecture - Science | Lecture Movie | Medicine - Practical | primordial germ cell | meiosis | Female | X | ovary | corpus luteum | oocyte | uterus | vagina | reproductive cycles | menstrual cycle | Male | Y | SRY | testis | spermatozoa | ductus deferens | penis | prostate | endocrine gonad‎ | Genital Movies | genital abnormalities | Assisted Reproductive Technology | puberty | Category:Genital
Historic Embryology - Genital 
1887-88 Testis | 1901 Urinogenital Tract | 1902 The Uro-Genital System | 1904 Ovary and Testis | 1904 Leydig Cells | 1904 Hymen | 1905 Testis vascular | 1909 Prostate | 1912 Prostate | 1912 Urinogenital Organ Development | 1914 External Genitalia | 1914 Female | 1915 Cowper’s and Bartholin’s Glands | 1920 Wolffian tubules | 1921 Urogenital Development | 1921 External Genital | 1927 Female Foetus 15 cm | 1932 Postnatal Ovary | 1935 Prepuce | 1935 Wolffian Duct | 1942 Sex Cords | 1943 Testes Descent | 1953 Germ Cells | Historic Embryology Papers | Historic Disclaimer
ICD10 - Gastrointestinal | Genital | Renal | Integumentary

ICD-10 Congenital malformations of genital organs (Q50-Q56) Excl.: androgen resistance syndrome (E34.5) syndromes associated with anomalies in the number and form of chromosomes (90-99) testicular feminization syndrome (E34.5)

ICD-10 Congenital malformations of ovaries, fallopian tubes and broad ligaments (Q50)

  • Q50.0 Congenital absence of ovary Excl.: Turner's syndrome (96.-)
  • Q50.1 Developmental ovarian cyst
  • Q50.2 Congenital torsion of ovary
  • Q50.3 Other congenital malformations of ovary Accessory ovary Congenital malformation of ovary NOS Ovarian streak
  • Q50.4 Embryonic cyst of fallopian tube Fimbrial cyst
  • Q50.5 Embryonic cyst of broad ligament Cyst: epoophoron Gartner's duct parovarian
  • Q50.6 Other congenital malformations of fallopian tube and broad ligament Absence Accessory Atresia (of) fallopian tube or broad ligament Congenital malformation of fallopian tube or broad ligament NOS

ICD-10 Congenital malformations of uterus and cervix (Q51)

  • Q51.0 Agenesis and aplasia of uterus Congenital absence of uterus
  • Q51.1 Doubling of uterus with doubling of cervix and vagina
  • Q51.2 Other doubling of uterus Doubling of uterus NOS
  • Q51.3 Bicornate uterus
  • Q51.4 Unicornate uterus
  • Q51.5 Agenesis and aplasia of cervix Congenital absence of cervix
  • Q51.6 Embryonic cyst of cervix
  • Q51.7 Congenital fistulae between uterus and digestive and urinary tracts
  • Q51.8 Other congenital malformations of uterus and cervix Hypoplasia of uterus and cervix
  • Q51.9 Congenital malformation of uterus and cervix, unspecified

ICD-10 Other congenital malformations of female genitalia (Q52)

  • Q52.0 Congenital absence of vagina
  • Q52.1 Doubling of vagina Septate vagina Excl.: doubling of vagina with doubling of uterus and cervix (51.1)
  • Q52.2 Congenital rectovaginal fistula Excl.: cloaca (43.7)
  • Q52.3 Imperforate hymen
  • Q52.4 Other congenital malformations of vagina Congenital malformation of vagina NOS Cyst: canal of Nuck, congenital embryonic vaginal
  • Q52.5 Fusion of labia
  • Q52.6 Congenital malformation of clitoris
  • Q52.7 Other congenital malformations of vulva Congenital: absence cyst malformation NOS of vulva
  • Q52.8 Other specified congenital malformations of female genitalia
  • Q52.9 Congenital malformation of female genitalia, unspecified

ICD-10 Undescended testicle (Q53)

  • Q53.0 Ectopic testis Unilateral or bilateral ectopic testes
  • Q53.1 Undescended testicle, unilateral
  • Q53.2 Undescended testicle, bilateral
  • Q53.9 Undescended testicle, unspecified Cryptorchism NOS

ICD-10 Hypospadias Template:Q54 Excl.: epispadias (64.0)

  • Q54.0 Hypospadias, balanic Hypospadias: coronal glandular
  • Q54.1 Hypospadias, penile
  • Q54.2 Hypospadias, penoscrotal
  • Q54.3 Hypospadias, perineal
  • Q54.4 Congenital chordee
  • Q54.8 Other hypospadias
  • Q54.9 Hypospadias, unspecified

ICD-10 Other congenital malformations of male genital organs (Q55)

Excl.: congenital hydrocele (P83.5) hypospadias (54.-)

  • Q55.0 Absence and aplasia of testis Monorchism
  • Q55.1 Hypoplasia of testis and scrotum Fusion of testes
  • Q55.2 Other congenital malformations of testis and scrotum Congenital malformation of testis or scrotum NOS Polyorchism Retractile testis Testis migrans
  • Q55.3 Atresia of vas deferens
  • Q55.4 Other congenital malformations of vas deferens, epididymis, seminal vesicles and prostate Absence or aplasia of: prostate spermatic cord Congenital malformation of vas deferens, epididymis, seminal vesicles or prostate NOS
  • Q55.5 Congenital absence and aplasia of penis
  • Q55.6 Other congenital malformations of penis Congenital malformation of penis NOS Curvature of penis (lateral) Hypoplasia of penis
  • Q55.8 Other specified congenital malformations of male genital organs
  • Q55.9 Congenital malformation of male genital organ, unspecified Congenital: anomaly deformity NOS of male genital organ

ICD-10 Indeterminate sex and pseudohermaphroditism (Q56) Online Editor - Note that the term "pseudohermaphroditism" has been replaced by DSD

Excl.: pseudohermaphroditism: female, with adrenocortical disorder (E25.-) male, with androgen resistance (E34.5) with specified chromosomal anomaly (96-99)

  • Q56.0 Hermaphroditism, not elsewhere classified Ovotestis
  • Q56.1 Male pseudohermaphroditism, not elsewhere classified Male pseudohermaphroditism NOS
  • Q56.2 Female pseudohermaphroditism, not elsewhere classified Female pseudohermaphroditism NOS
  • Q56.3 Pseudohermaphroditism, unspecified
  • Q56.4 Indeterminate sex, unspecified Ambiguous genitalia

Please note that this category uses old terminology, that has been replaced elsewhere with "Disorders of Sex Development (DSD)".


Ultrasonographic and multimodal imaging of pediatric genital female diseases

J Ultrasound. 2019 Feb 19. doi: 10.1007/s40477-019-00358-5. [Epub ahead of print]

Caprio MG1, Di Serafino M2, De Feo A3, Guerriero E3, Perillo T3, Barbuto L4, Vezzali N5, Rossi E6, Ferro F5, Vallone G7, Orazi C8. Author information Abstract Ultrasonography is the first-line imaging modality in the evaluation of the female pelvis in childhood and adolescence, because it is easy to perform, non-invasive and it does not require sedation. The transabdominal approach is preferred in children and adolescents, after filling the bladder to move away the bowel loops from the pelvis. The probe frequency must be adapted to age, thickness of tissues and depth of the structures under examination. High-frequency (4-12 MHz) linear or convex probes are used in newborns; high-frequency linear probes (4-12 MHz) in toddler, convex 5-7.5 MHz probes in girls and convex 3.5-5 MHz probes in teenagers. In this article, the main pathological conditions of the genital female tract in pediatric age are examined, such as congenital anomalies, disorders of sex development, ovarian cysts, ovarian tumors, adnexal torsion, primary amenorrhea, precocious puberty and pelvic inflammatory disease. KEYWORDS: Congenital anomalies; Disorders of sex development; Genital female tract; Pediatric age; Pelvic expansive masses; Ultrasound examination PMID: 30778893 DOI: 10.1007/s40477-019-00358-5

2018

Variations of sex development: The first German interdisciplinary consensus paper

J Pediatr Urol. 2018 Nov 17. pii: S1477-5131(18)30616-8. doi: 10.1016/j.jpurol.2018.10.008. [Epub ahead of print]

Krege S1, Eckoldt F2, Richter-Unruh A3, Köhler B4, Leuschner I5, Menzel HJ6, Moss A7, Schweizer K8, Stein R9, Werner-Rosen K10, Wieacker P11, Wiesemann C12, Wünsch L13, Richter-Appelt H8. Author information Abstract INTRODUCTION: The term variations of sex development subsumes a large number of congenital conditions including chromosomal mosaics and variations of chromosomal, gonadal, and phenotypic sex. A situation of this nature may cause severe distress to both, parents and affected persons. One of the reasons for this is the binary form of gender classification in the society. In the past, because of a fear of possible stigmatization and an inability to cope with complex situations, it has been medical policy and practice for newborns to undergo early, mostly 'feminizing' elective surgery with the aim of achieving an outer genital appearance that is unambiguously male or female. Protests by advocacy groups for the most part as well as the results of outcome studies have shown that the development of affected persons may be very different to what has been expected and often does not result in the intended clear female or male gender identity as had been intended. It, therefore, seemed a matter of urgency to implement this new awareness as well as the ethical and personal human rights perspectives in the recommendations for the medical and psychosocial management of diverse sex development (DSD) in the future. STUDY DESIGN: In 2012, an interdisciplinary group of German academics engaged in the field of DSD decided to work on a consensus paper for this topic. It involved the participation of all faculties and non-scientific groups dealing with DSD, in particular advocacy and service-user groups. In a structured consensus, process recommendations were developed based on scientific literature as well as personal experiences of clinicians and affected individuals. RESULTS: Finally, 37 recommendations were agreed on. The strength of consensus is reflected in the degree of agreement as expressed in percentages. CONCLUSION: The introduction of the consensus paper reflects on the emerging paradigm shift and the necessity for a more open view of gender within society. The paper is intended to aid the performance of appropriate diagnostics in DSD-affected newborns and especially to help parents and affected persons cope with the biological and social consequences of DSD. With regard to medical or surgical therapy, it gives information about the most recent treatment trends. Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. KEYWORDS: Consensus paper; DSD; Diagnostic and treatment approaches; Diverse sex development; Intersex PMID: 30713084 DOI: 10.1016/j.jpurol.2018.10.008

Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study

Indian J Endocrinol Metab. 2018 Nov-Dec;22(6):774-779. doi: 10.4103/ijem.IJEM_159_18.

Dar SA1, Nazir M1, Lone R2, Sameen D3, Ahmad I1, Wani WA1, Charoo BA1. Author information Abstract OBJECTIVE: Disorders of sex development (DSD) constitutes a small but difficult and equally important area of endocrinology. It is often a social emergency as the decision regarding sex assignment in these cases is extremely disturbing and difficult to both families and healthcare professionals. Our study was devised to assess the clinical and chromosomal profile of patients with suspected DSD and classify them according to the new DSD consensus document. SUBJECTS AND METHODS: This study was a cross-sectional observational study carried out in the department of pediatrics of a tertiary care hospital from August 2012 to August 2014. All patients with suspected DSD in the age group of 0-19 years were included. After detailed history and examination, karyotyping, abdominal sonography, and hormonal analysis were done. Additional studies like gonadal biopsy, laparoscopy, and hormone stimulation tests were done in selected cases. RESULTS: About 41 patients were included in the study. The mean age of presentation was 87 months (1 day to 16 years). Only seven (13.7%) patients presented in neonatal period. In total, 25 patients had ambiguous genitalia; 46, XX DSD were diagnosed in 24 (58.5%) patients, 46, XY DSD in 10 (24.4%) patients, and sex chromosome DSD in 7 (17.1%). Congenital adrenal hyperplasia (CAH) was the commonest disease diagnosed in 21 (51.2%) patients. Turner syndrome, Klinefelter syndrome, androgen insensitivity syndrome, 46, XX ovotesticular disorder, and 46, XY gonadal dysgenesis were diagnosed in 3, 3, 4, 3, and 5 patients, respectively. Eleven patients with CAH presented in shock and six had history of sib deaths. CONCLUSION: 46, XX DSD were the commonest etiological group in our study and CAH was the commonest individual disease. There is a need for educating general public and practitioners regarding DSD to allow early intervention. Moreover, there is a need to introduce routine neonatal screening for CAH in our country. KEYWORDS: Congenital adrenal hyperplasia; hermaphroditism; intersex; karyotype

A collection of XY female cell lines

Hum Cell. 2018 Jan 12. doi: 10.1007/s13577-017-0195-5.

Kasai F1,2, Ferguson-Smith MA3.

Abstract

Discordance between sexual phenotype and the 46,XY sex chromosome complement may be found in certain disorders of sexual development (DSD). Many of these DSD patients with female external genitalia and secondary sex characteristics have undescended testes and male internal genitalia. Causative mutations involving genes of the sex determining pathway, including the androgen receptor, SRY and the 5-alpha-reductase genes, are well-known, but the origin of other cases remain unresolved. In this report, we introduce our collection of lymphoblastoid lines derived from female patients with a 46,XY karyotype. These cell lines have been deposited and registered with the JCRB Cell Bank. They are available for comparison with other DSD cases and for further characterization of genetic loci involved in the mammalian sex determining pathway. KEYWORDS: Disorder of sexual development; EB virus-transformed lymphoblastoid cell line; Patient-derived cell resource; Sex determination; Sex reversal

PMID: 29330774 DOI: 10.1007/s13577-017-0195-5

2017

Hypospadias, all there is to know

Eur J Pediatr. 2017 Apr;176(4):435-441. doi: 10.1007/s00431-017-2864-5. Epub 2017 Feb 11.

van der Horst HJ1, de Wall LL2.

Erratum in Erratum to: hypospadias, all there is to know. [Eur J Pediatr. 2017]

Abstract

Hypospadias is one of the most common congenital anomalies in men. The condition is typically characterized by proximal displacement of the urethral opening, penile curvature, and a ventrally deficient hooded foreskin. In about 70%, the urethral meatus is located distally on the penile shaft; this is considered a mild form that is not associated with other urogenital deformities. The remaining 30% are proximal and often more complex. In these cases, endocrinological evaluation is advised to exclude disorders of sexual differentiation, especially in case of concomitant unilateral or bilateral undescended testis. Although the etiology of hypospadias is largely unknown, many hypotheses exist about genetic predisposition and hormonal influences. The goal of hypospadias repair is to achieve cosmetic and functional normality, and currently, surgery is recommended between 6 and 18 months of age. Hypospadias can be corrected at any age with comparable complication risk, functional, and cosmetic outcome; however, the optimal age of repair remains conclusive. Although long-term overall outcome concerning cosmetic appearance and sexual function is fairly good, after correction, men may more often be inhibited in seeking sexual contact. Moreover, lower urinary tract symptoms occur twice as often in patients undergoing hypospadias repair and can still occur many years after the initial repair. CONCLUSION: This study explores the most recent insights into the management of hypospadias. What is Known: • Guidelines advise referral for treatment between 6 and 18 months of age. • Cosmetic outcome is considered satisfactory in over 70% of all patients. What is New: • Long-term complications include urinary tract symptoms and sexual and cosmetic issues. • New developments allow a more individualized approach, hopefully leading to less complications and more patient satisfaction. KEYWORDS: Algorithm; Conservative management; Disorders of sex development; Hypospadias; Referral; Timing of treatment; Tissue engineering PMID: 28190103 PMCID: PMC5352742 DOI: 10.1007/s00431-017-2864-5 [Indexed for MEDLINE] Free PMC Article


Altered SOX9 genital tubercle enhancer region in hypospadias

J Steroid Biochem Mol Biol. 2017 Jun;170:28-38. doi: 10.1016/j.jsbmb.2016.10.009. Epub 2016 Oct 29.

Sreenivasan R1, Gordon CT2, Benko S2, de Iongh R3, Bagheri-Fam S4, Lyonnet S2, Harley V5.

Abstract

Human mutations in the SOX9 gene or its regulatory region can disrupt testicular development, leading to disorders of sex development (DSDs). Our previous work involving the genomic analysis of isolated DSD patients revealed a 78kb minimal sex determining region (RevSex) far upstream of SOX9 that was duplicated in 46,XX and deleted in 46,XY DSDs. It was postulated that RevSex contains a gonadal enhancer. However, the most highly conserved sub-region within RevSex, called SR4, was neither responsive to sex determining factors in vitro nor active in the gonads of transgenic mice, suggesting that SR4 may not be functioning as a testicular enhancer. Interestingly, SR4 transgenic mice showed reporter activity in the genital tubercle, the primordium of the penis and clitoris, a previously unreported domain of Sox9 expression. SOX9 protein was detected in the genital tubercle, notably in the urethral plate epithelium, preputial glands, ventral surface ectoderm and corpus cavernosa. SR4 may therefore function as a Sox9 genital tubercle enhancer, mutations of which could possibly lead to hypospadias, a birth defect seen in the DSD patients in the RevSex study. SR4 activity and the observed SOX9 expression pattern suggest that SR4 may function as a Sox9 genital tubercle enhancer. However, conditional ablation of Sox9 in the genital tubercle using Shh-Cre/+;Sox9flox/flox mice revealed no genital tubercle abnormalities, possibly due to compensation by similar Sox factors. To conclude, we have identified a novel regulatory enhancer driving Sox9 expression during external genitalia development. Copyright © 2016 Elsevier Ltd. All rights reserved.

KEYWORDS: Disorder of sex development; Enhancer; Genital tubercle; Hypospadias; SOX9 PMID 27989796 DOI: 10.1016/j.jsbmb.2016.10.009


2016

Systematization of ambiguous genitalia

Organogenesis. 2016 Jul 8:1-14. [Epub ahead of print]

Makiyan Z.

Abstract

Sex assignment in newborns depends on the anatomy of the external genitalia, despite this stage being the final in embryogenesis. According to the current view, the genital tubercle is the embryonic precursor of penis and clitoris. It originates from mesenchymal tissue, but mesenchymal cells are arranged across the embryonal body and do not have specific androgen receptors. The nature of the signal that initiates early derivation of the indifferent genital tubercle is unknown at present. The aims of this article are to improve surgical management of intersex disorders and investigate the development of the genital tubercle. Clinical examination of 114 females with various forms of DSD revealed ambiguous (bisexual) external genitalia in 73 patients, and 51 of them underwent feminizing surgery. Intersexuality (ambiguity) in 46,XY patients results from disruptors in the pathways of sex steroid hormones or receptors; in 46,XX females arises from excessive levels of androgens. Systematization of intersex disorders distinguishes the karyotype, gonadal morphology, and genital anatomy to provide a differential diagnosis and guide appropriate surgical management. Modified feminizing clitoroplasty with preservation of the dorsal and ventral neurovascular bundles to retain erogenous sensitivity was performed in females with severe virilization (Prader degree III-V). The outgrowth of the genital tubercle and the fusion of the urethral fold proceed in an ordered fashion; but in some cases of ambiguity, there was discordance due to different pathways. Speculation about the derivation of the genital tubercle have discussed with a literature review. The genital tubercle derives from the following 3 layers: the ectodermal glans of the tubercle, the mesodermal corpora cavernosa and the endodermal urogenital groove. According to the new hypothesis, during the indifferent stages, the 5 sacral somites have to recede from their segmentation and disintegrate: the sclerotomes form the pelvic bones, the fused myotomes follow with their genuine neurotomes and the angiotomes join to the corpora cavernosa of the genital tubercle. Sexual differentiation of external genitalia is final in gender embryogenesis, but surprisingly derivation of the indifferent genital tubercle from 5 somites occurs before gonadal and internal organs development. KEYWORDS: ambiguity; cliitororeduction; disorders of sex development; embryogenesis of external genitalia; erogenous sensitivity; feminizing plasty; genital tubercle; intersexuality

PMID 27391116

Congenital Adrenal Hyperplasia
Type Enzyme Deficiency Female Male
classic virilizing adrenal hyperplasia 21-hydroxylase, 11-beta-hydroxylase,
or 3-beta-hydroxysteroid dehydrogenase
ambiguous genitalia at birth - complete or partial fusion of the labioscrotal folds and a phallic urethra to clitoral enlargement (clitoromegaly), partial fusion of the labioscrotal folds, or both normal genitalia, present at age 1-4 weeks with salt wasting (classic salt-wasting adrenal hyperplasia)
simple virilizing adrenal hyperplasia mild 21-hydroxylase identified later in childhood because of precocious pubic hair, clitoral enlargement (clitoromegaly), or both, often accompanied by accelerated growth and skeletal maturation early genital development (pubic hair and/or phallic enlargement) accelerated growth and skeletal maturation
nonclassic adrenal hyperplasia milder deficiencies of 21-hydroxylase
or 3-beta-hydroxysteroid dehydrogenase
present at puberty or adult with infrequent menstruation (oligomenorrhea), abnormal hair growth (hirsutism), and/or infertility
17-hydroxylase deficiency syndrome 17-hydroxylase deficiency or

3-beta-hydroxysteroid dehydrogenase

rare, phenotypically female at birth do not develop breasts or menstruate in adolescence and may have hypertension steroidogenic acute regulatory (StAR) deficiency have ambiguous genitalia or female genitalia, at puberty may lack breast development and may have hypertension
This is a complex steroidogenic abnormality, and the above table of clinical descriptions are provided only a guide.
Links: Genital Abnormalities | Adrenal Development | Genes and Disease | OMIM 21 Deficiency | OMIM 17 Deficiency | OMIM 3 Deficiency

Decreased production of glucocorticoids and sex steroids, resulting in sexual infantilism in 46,XX females and ambiguous genitalia in 46,XY males

2015

Tissue-specific roles of Fgfr2 in development of the external genitalia

Development. 2015 Jun 15;142(12):2203-12. doi: 10.1242/dev.119891.

Gredler ML1, Seifert AW1, Cohn MJ2. Author information Abstract Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis. In the genital tubercle, the embryonic precursor of the penis and clitoris, Fgfr2 is expressed in two epithelial populations: the endodermally derived urethral epithelium and the ectodermally derived surface epithelium. Here, we investigate the tissue-specific roles of Fgfr2 in external genital development by generating conditional deletions of Fgfr2 in each of these cell types. Conditional deletion of Fgfr2 results in two distinct phenotypes: endodermal Fgfr2 deletion causes mild hypospadias and inhibits maturation of a complex urethral epithelium, whereas loss of ectodermal Fgfr2 results in severe hypospadias and absence of the ventral prepuce. Although these cell type-specific mutants exhibit distinctive genital anomalies, cellular analysis reveals that Fgfr2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm. The unexpected finding that ectodermal deletion of Fgfr2 results in the most severe hypospadias highlights a major role for Fgfr2 in the developing genital surface epithelium, where epithelial maturation is required for maintenance of a closed urethral tube. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: Fgf; Genitalia; Mouse; Sexual differentiation; Tubulogenesis; Urethra PMID: 26081573 PMCID: PMC4483768 DOI: 10.1242/dev.119891

The perinatal origins of major reproductive disorders in the adolescent: Research avenues

Placenta. 2015 Apr;36(4):341-4. doi: 10.1016/j.placenta.2015.01.003. Epub 2015 Jan 15.

Brosens I1, Ćurčić A2, Vejnović T2, Gargett CE3, Brosens JJ4, Benagiano G5.

Abstract

The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies. Copyright © 2015 Elsevier Ltd. All rights reserved. KEYWORDS: Endometriosis; Endometrium; Neonatal uterine bleeding; Obstetrical disorders; Progesterone resistance

PMID 25637411


2013

Minor hypospadias: the "tip of the iceberg" of the partial androgen insensitivity syndrome

PLoS One. 2013 Apr 30;8(4):e61824. doi: 10.1371/journal.pone.0061824. Print 2013.

Kalfa N, Philibert P, Werner R, Audran F, Bashamboo A, Lehors H, Haddad M, Guys JM, Reynaud R, Alessandrini P, Wagner K, Kurzenne JY, Bastiani F, Bréaud J, Valla JS, Lacombe GM, Orsini M, Daures JP, Hiort O, Paris F, McElreavey K, Sultan C. Source Service de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France ; Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.

Abstract

BACKGROUND: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS). OBJECTIVE: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. MATERIALS AND METHODS: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants. RESULTS: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient. CONCLUSION: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

PMID 23637914

Nationwide Prevalence of Groin Hernia Repair

PLoS ONE 8(1): e54367. doi:10.1371/journal.pone.0054367 (2013)

Burcharth J, Pedersen M, Bisgaard T, Pedersen C, Rosenberg J


Groin hernia repair is a commonly performed surgical procedure in the western world but large-scaled epidemiologic data are sparse. Large-scale data on the occurrence of groin hernia repair may provide further understanding to the pathophysiology of groin hernia development. This study was undertaken to investigate the age and gender dependent prevalence of groin hernia repair.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054367


2012

NIH - Evidence-based Methodology Workshop on Polycystic Ovary Syndrome December 3–5, 2012 PCOS Draft Statement PDF

2011

The history of female genital tract malformation classifications and proposal of an updated system

Hum Reprod Update. 2011 Sep-Oct;17(5):693-705. Epub 2011 Jul 4.

Acién P, Acién MI. Source Service of Obstetrics and Gynaecology, Department of Gynaecology, University Hospital of San Juan, Alicante, Spain. acien@umh.es

Abstract

BACKGROUND: A correct classification of malformations of the female genital tract is essential to prevent unnecessary and inadequate surgical operations and to compare reproductive results. An ideal classification system should be based on aetiopathogenesis and should suggest the appropriate therapeutic strategy. METHODS: We conducted a systematic review of relevant articles found in PubMed, Scopus, Scirus and ISI webknowledge, and analysis of historical collections of 'female genital malformations' and 'classifications'. Of 124 full-text articles assessed for eligibility, 64 were included because they contained original general, partial or modified classifications. RESULTS: All the existing classifications were analysed and grouped. The unification of terms and concepts was also analysed. Traditionally, malformations of the female genital tract have been catalogued and classified as Müllerian malformations due to agenesis, lack of fusion, the absence of resorption and lack of posterior development of the Müllerian ducts. The American Fertility Society classification of the late 1980s included seven basic groups of malformations also considering the Müllerian development and the relationship of the malformations to fertility. Other classifications are based on different aspects: functional, defects in vertical fusion, embryological or anatomical (Vagina, Cervix, Uterus, Adnex and Associated Malformation: VCUAM classification). However, an embryological-clinical classification system seems to be the most appropriate. CONCLUSIONS: Accepting the need for a new classification system of genitourinary malformations that considers the experience gained from the application of the current classification systems, the aetiopathogenesis and that also suggests the appropriate treatment, we proposed an update of our embryological-clinical classification as a new system with six groups of female genitourinary anomalies.

PMID 21727142


Disorders of sex development-when and how to tell the patient

Austin J, Tamar-Mattis A, Mazur T, Henwood MJ, Rossi WC. Pediatr Endocrinol Rev. 2011 Mar;8(3):213-7; quiz 223.

Abstract Physicians and other providers are often confronted with difficult decisions in the area of disclosure. This article examines a hypothetical situation relevant to the practice of pediatric endocrinology. The parents of a child with a disorder of sex development (DSD) wish the physician to treat their child, but without revealing key medical information to the child. Herein, we will explore the legal and ethical responsibilities of a provider to disclose information to an under-age DSD patient and to provide insight on when and how to tell the patient.

PMID 21525798

The Relationship between Anogenital Distance, Fatherhood, and Fertility in Adult Men

Eisenberg ML, Hsieh MH, Walters RC, Krasnow R, Lipshultz LI.

PLoS One. 2011 May 11;6(5):e18973.

Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. ANOVA and linear regression were used to determine correlations between AGD, fatherhood status, and semen analysis parameters (sperm density, motility, and total motile sperm count). Findings

A total of 117 infertile men (mean age: 35.3±17.4) and 56 fertile men (mean age: 44.8±9.7) were recruited. The infertile men possessed significantly shorter mean AGD and PL compared to the fertile controls (AGD: 31.8 vs 44.6 mm, PL: 107.1 vs 119.5 mm, p<0.01). The difference in AGD persisted even after accounting for ethnic and anthropomorphic differences. In addition to fatherhood, on both unadjusted and adjusted linear regression, AGD was significantly correlated with sperm density and total motile sperm count. After adjusting for demographic and reproductive variables, for each 1 cm increase in a man's AGD, the sperm density increases by 4.3 million sperm per mL (95% CI 0.53, 8.09, p=0.03) and the total motile sperm count increases by 6.0 million sperm (95% CI 1.34, 10.58, p=0.01). On adjusted analyses, no correlation was seen between penile length and semen parameters.

Conclusion

A longer anogenital distance is associated with fatherhood and may predict normal male reproductive potential. Thus, AGD may provide a novel metric to assess reproductive potential in men.

PMID 21589916

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092750

Pictorial essay: Congenital anomalies of male urethra in children

Indian J Radiol Imaging. 2011 Jan;21(1):38-45.

Jana M, Gupta AK, Prasad KR, Goel S, Tambade VD, Sinha U. Source Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

Abstract

Congenital anomalies of the male urogenital tract are common. Some lesions like posterior urethral valve or anterior urethral diverticulum tend to present early in infancy and are often easily diagnosed on conventional contrast voiding cystourethrograms. Other conditions like posterior urethral diverticulum or utricle can be relatively asymptomatic and therefore present late in childhood. We present the spectrum of imaging findings of common and uncommon anomalies involving the male urethra. Since the pediatric radiologist is often the first to make the diagnosis, he or she should be well aware of these conditions.

PMID 21431032

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056369

2010

Consensus in Guidelines for Evaluation of DSD by the Texas Children's Hospital Multidisciplinary Gender Medicine Team

Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Int J Pediatr Endocrinol. 2010;2010:919707. Epub 2010 Oct 17.

The Gender Medicine Team (GMT), comprised of members with expertise in endocrinology, ethics, genetics, gynecology, pediatric surgery, psychology, and urology, at Texas Children's Hospital and Baylor College of Medicine formed a task force to formulate a consensus statement on practice guidelines for managing disorders of sexual differentiation (DSD) and for making sex assignments. The GMT task force reviewed published evidence and incorporated findings from clinical experience. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to assess the quality of evidence presented in the literature for establishing evidence-based guidelines. The task force presents a consensus statement regarding specific diagnostic and therapeutic issues in the management of individuals who present with DSD. The consensus statement includes recommendations for (1) laboratory workup, (2) acute management, (3) sex assignment in an ethical framework that includes education and involvement of the parents, and (4) surgical management.

PMID 20981291

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963131


46,XY DSD with Female or Ambiguous External Genitalia at Birth due to Androgen Insensitivity Syndrome, 5alpha-Reductase-2 Deficiency, or 17beta-Hydroxysteroid Dehydrogenase Deficiency: A Review of Quality of Life Outcomes

Int J Pediatr Endocrinol. 2009;2009:567430. Epub 2009 Sep 10.

Wisniewski AB, Mazur T.

Section of Pediatric Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 NE 13th Street, Room 2B2426, Oklahoma City, OK 73117, USA.

Abstract Disorders of sex development refer to a collection of congenital conditions in which atypical development of chromosomal, gonadal, or anatomic sex occurs. Studies of 46,XY DSD have focused largely on gender identity, gender role, and sexual orientation. Few studies have focused on other domains, such as physical and mental health, that may contribute to a person's quality of life. The current review focuses on information published since 1955 pertaining to psychological well-being, cognition, general health, fertility, and sexual function in people affected by androgen insensitivity syndromes, 5-alpha reductase-2 deficiency, or 17beta-hydroxysteroid dehydrogenase-3 deficiency-reared male or female. The complete form of androgen insensitivity syndrome has been the focus of the largest number of investigations in domains other than gender. Despite this, all of the conditions included in the current review are under-studied. Realms identified for further study include psychological well-being, cognitive abilities, general health, fertility, and sexual function. Such investigations would not only improve the quality of life for those affected by DSD but may also provide information for improving physical and mental health in the general population.

PMID 19956704

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777017

Special Issue: Klinefelter's Syndrome: basic science to clinic

MHR: Basic science of reprod. MedicineVolume16, Issue6

Volume 16 Issue 6 June 2010

http://molehr.oxfordjournals.org/content/16/6.toc


Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents

Eur J Pediatr. 2010 Jun;169(6):671-9. Epub 2009 Oct 20.

Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U.

Department for Medical Ethics and History of Medicine, Göttingen University, Humboldtallee 36, 37073 Göttingen, Germany. cwiesem@gwdg.de Abstract The medical management of differences of sex development (DSD)/intersex in early childhood has been criticized by patients' advocates as well as bioethicists from an ethical point of view. Some call for a moratorium of any feminizing or masculinizing operations before the age of consent except for medical emergencies. No exhaustive ethical guidelines have been published until now. In particular, the role of the parents as legal representatives of the child is controversial. In the article, we develop, discuss, and present ethical principles and recommendations for the medical management of intersex/DSD in children and adolescents. We specify three basic ethical principles that have to be respected and substantiate them. The article includes a critical discussion of the best interest of the child and of family privacy. The argumentation draws upon recommendations by the working group "Bioethics and Intersex" within the German Network DSD/Intersex, which are presented in detail. Unlike other recommendations with regard to intersex, these guidelines represent a comprehensive view of the perspectives of clinicians, patients, and their families. CONCLUSION: The working group identified three leading ethical principles that apply to DSD management: (1) to foster the well-being of the child and the future adult, (2) to uphold the rights of children and adolescents to participate in and/or self-determine decisions that affect them now or later, and (3) to respect the family and parent-child relationships. Nine recommendations for the management of DSD indicate how these ethical principles can spelled out and balanced against each other in the clinical setting.

PMID 19841941

2009

The exstrophy-epispadias complex

Orphanet J Rare Dis. 2009 Oct 30;4:23.

Ebert AK, Reutter H, Ludwig M, Rösch WH.

Department of Pediatric Urology, University Medical Center Regensburg, Germany. anne-karoline.ebert@barmherzige-regensburg.de Abstract Exstrophy-epispadias complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) to classical bladder exstrophy (CEB) and exstrophy of the cloaca (EC). Depending on severity, EEC may involve the urinary system, musculoskeletal system, pelvis, pelvic floor, abdominal wall, genitalia, and sometimes the spine and anus. Prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males. EEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). In CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. EEC results from mechanical disruption or enlargement of the cloacal membrane; the timing of the rupture determines the severity of the malformation. The underlying cause remains unknown: both genetic and environmental factors are likely to play a role in the etiology of EEC. Diagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally by ultrasound from repeated non-visualization of a normally filled fetal bladder. Counseling should be provided to parents but, due to a favorable outcome, termination of the pregnancy is no longer recommended. Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Several methods for bladder reconstruction with creation of an outlet resistance during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Additional surgery might be needed to optimize bladder storage and emptying function. In cases of final reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function are important issues. Psychosocial and psychosexual outcome depend on long-term multidisciplinary care to facilitate an adequate quality of life.

PMID 19878548

http://www.ojrd.com/content/4/1/23


Critical windows of exposure for children's health: the reproductive system in animals and humans

Environ Health Perspect. 2000 Jun;108 Suppl 3:491-503.


Pryor JL, Hughes C, Foster W, Hales BF, Robaire B.

University of Minnesota Medical School, Minneapolis, Minnesota, USA. Abstract Drugs and environmental chemicals can adversely affect the reproductive system. Currently, available data indicate that the consequences of exposure depend on the nature of the chemical, its target, and the timing of exposure relative to critical windows in development of the reproductive system. The reproductive system is designed to produce gametes in far greater excess than would seem to be necessary for the survival of species. Ten to hundreds of millions of spermatozoa are generated daily by most adult male mammals, yet very few of these germ cells succeed in transmitting their genetic material to the next generation. Although the number of oocytes produced in mammalian females is more limited, and their production occurs only during fetal life, most ovaries contain several orders of magnitude more oocytes than ever will be fertilized. Toxicant exposures may affect critical events in the development of the reproductive system, ranging from early primordial germ cell determination to gonadal differentiation, gametogenesis, external genitalia, or signaling events regulating sexual behavior. Although there are differences between the human reproductive system and that of the usual animal models, such models have been extremely useful in assessing risks for key human reproductive and developmental processes. The objectives for future studies should include the elucidation of the specific cellular and molecular targets of known toxicants; the design of a systematic approach to the identification of reproductive toxicants; and the development of sensitive, specific, and predictive animal models, minimally invasive surrogate markers, or in vitro tests to assess reproductive system function during embryonic, postnatal, and adult life.

PMID 10852849

2007

Polycystic ovary syndrome and its developmental origins

Rev Endocr Metab Disord. 2007 Jun;8(2):127-41.

Dumesic DA, Abbott DH, Padmanabhan V. Source Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA. danieldumesic@aol.com

Abstract

The prenatal testosterone (T)-treated adult female rhesus monkey is one animal model of polycystic ovary syndrome (PCOS) in women, with early prenatal T excess programming a permanent PCOS-like phenotype characterized by luteinizing hormone (LH) hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess from increased abdominal adiposity. These combined reproductive and metabolic abnormalities are associated with ovarian hyperandrogenism and follicular arrest in adulthood, as well as premature follicle differentiation and impaired embryo development during gonadotropin therapy for in vitro fertilization (IVF). A second animal model for PCOS, the prenatal T-treated sheep also is characterized by LH hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback, persistent follicles and insulin resistance, but also is associated with intrauterine growth retardation and compensatory growth after birth. The ability of prenatal T excess in both species to alter the developmental trajectory of multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programs target tissue differentiation, raising the possibility that T excess in human fetal development promotes PCOS in adulthood. Such a hypothesis must include data from clinical studies of PCOS women to clarify the homology between these PCOS-like animal models and PCOS per se in reproductive and metabolic function. Future studies should develop new clinical strategies that improve pregnancy outcome and minimize pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus as well as minimize transgenerational susceptibility to adult PCOS and its metabolic derangements in male close relatives.

PMID 17659447

Age-specific changes in sex steroid biosynthesis and sex development

Best Pract Res Clin Endocrinol Metab. 2007 Sep;21(3):393-401.


Krone N, Hanley NA, Arlt W. Source Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Abstract

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.

PMID 17875487