Genital - Male Development

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Introduction

Human Y chromosome SRY region.jpg
Urogenital male structures cartoon
Urogenital Male

The male and female reproductive systems develop initially "indifferently", it is the product of the Y chromosome SRY gene that makes the "difference". The mesonephric duct (Wolffian Duct) contributes the majority of male internal genital tract.


Embryonic gonad development leads to the mesonephric/paramesonephric duct changes, while the external genitaila remain indeterminate in appearance through to the fetal period.


Importantly its sex chromosome dependence, late embryonic/fetal differential development, complex morphogenic changes, long time-course, hormonal sensitivity and hormonal influences make it a system prone to many different abnormalities.


There are also separate pages describing: spermatozoa | testis | prostate | Y Chromosome | Category:Male


Genital Links: genital | Lecture - Medicine | Lecture - Science | Lecture Movie | Medicine - Practical | primordial germ cell | meiosis | Female | X | ovary | oocyte | uterus | vagina | reproductive cycles | menstrual cycle | Male | Y | testis | spermatozoa | penis | prostate | Genital Movies | genital abnormalities | Assisted Reproductive Technology | puberty | Category:Genital
Historic Embryology - Genital 
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

Some Recent Findings

Male urogenital histology
Male urogenital development (week 8, stage 22)
  • Tissue-specific roles of Fgfr2 in development of the external genitalia[1] "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. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity." Fibroblast Growth Factor
  • Penile biometry on prenatal MR imaging [2]"Mean length values, including 95% confidence intervals and percentiles, were defined. Penile length as a function of gestational age was expressed by the regression equation: outer mean length= -5.514 + 0.622 *, and total mean length= -8.865 + 1.312 * (*= gestational weeks). The correlation coefficients were statistically significant (p < .001). The comparison between outer length on MRI and US data showed no significant differences, whereas total length on MRI and US data demonstrated significant differences (p< .001)."
  • Male reproductive tract abnormalities: More common after assisted reproduction?[3] "IVF and ICSI, by increasing the risks of prematurity, low birthweight, and multiple gestation, are indirect risk factors for developing male genital malformations. In infants with normal birhtweight or from singleton pregnancies, ICSI is a specific risk factor for hypospadias."
  • Temporal and spatial dissection of Shh signaling in genital tubercle development.[4] "Genital tubercle (GT) initiation and outgrowth involve coordinated morphogenesis of surface ectoderm, cloacal mesoderm and hindgut endoderm. GT development appears to mirror that of the limb. Although Shh is essential for the development of both appendages, its role in GT development is much less clear than in the limb. Here, by removing Shh at different stages during GT development in mice, we demonstrate a continuous requirement for Shh in GT initiation and subsequent androgen-independent GT growth."
  • Bmp7 expression and null phenotype in the urogenital system suggest a role in re-organization of the urethral epithelium. [5] "Signaling by Bone morphogenetic proteins (Bmps) has multiple and diverse roles in patterning and morphogenesis of the kidney, eye, limbs and the neural tube. ...Together, our analysis of Bmp7 expression and the null phenotype, indicates that Bmp7 may play an important role in re-organization of the epithelium during cloacal septation and morphogenesis of the genital tubercle."
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Male Embryology

Abdullah Ilhan, Umit Yolcu, Emin Oztas, Uzeyir Erdem Therapeutic effects of proanthocyanidin and coenzyme Q10 on nitrogen mustard-induced ocular injury. Arq Bras Oftalmol: 2018, 81(3);226-231 PubMed 29924193

D Maciejewska, K Skonieczna-Zydecka, A Lukomska, I Gutowska, K Dec, P Kupnicka, J Palma, A Pilutin, W Marlicz, E Stachowska The short chain fatty acids and lipopolysaccharides status in Sprague-Dawley rats fed with high-fat and high-cholesterol diet. J. Physiol. Pharmacol.: 2018, 69(2); PubMed 29920474

Mojtaba Ameli, Mohaddeseh Sadat Hashemi, Maryam Moghimian, Majid Shokoohi Protective effect of tadalafil and verapamil on testicular function and oxidative stress after torsion/detorsion in adult male rat. Andrologia: 2018;e13068 PubMed 29917246

P Naina, Mary John, Mohamed Abdul Kathar, Manish Kumar Tracheal agenesis in a new born: lessons learnt. BMJ Case Rep: 2018, 2018; PubMed 29914900

Textbooks

Historic drawing of the testis
Historic drawing of the testis
  • Human Embryology (2nd ed.) Larson Chapter 10 p261-306
  • The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Chapter 13 p303-346
  • Before We Are Born (5th ed.) Moore and Persaud Chapter 14 p289-326
  • Essentials of Human Embryology, Larson Chapter 10 p173-205
  • Human Embryology, Fitzgerald and Fitzgerald Chapter 21-22 p134-152
  • Developmental Biology (6th ed.) Gilbert Chapter 14 Intermediate Mesoderm


Movies

Gonad-icon.jpg
 ‎‎Testis
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Urogenital septum 001 icon.jpg
 ‎‎Urogenital Septum
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Male external 001 icon.jpg
 ‎‎Male External
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Testis 001 icon.jpg
 ‎‎Testis Descent
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Gonad blood 01 icon.jpg
 ‎‎Gonad Vascular
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Mouse Primordial Germ Cell Migration
Primordial germ cell 001 icon.jpg
 ‎‎Germ Cell E9.0
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Primordial germ cell 002 icon.jpg
 ‎‎Germ Cell E9.5
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Primordial germ cell 003 icon.jpg
 ‎‎Germ Cell E10.5
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Development Overview

Three main stages during development, mesonephric/paramesonephric duct changes are one of the first male/female differences that occur in development, while external genitaila remain indeterminate in appearance for quite a while.

  1. Differentiation of gonad (Sex determination)
  2. Differentiation of internal genital organs
  3. Differentiation of external genital organs

The 2nd and 3rd stages dependent on endocrine gonad. Reproductive development has a long maturation timecourse, begining in the embryo and finishing in puberty. (More? Puberty Development)

Historic Images of Genital Changes

Urogenital Indifferent Urogenital Male Urogenital Female
Urogenital indifferent Urogenital male Urogenital female

Gonad - Testis

See the detailed notes on testis development.

Links: Testis Development

Internal Genital

Mesonephric duct or Wolffian duct differentiates to form the male internal genital tract the vas deferens (ductus deferens, vas deferens or simply vas). Associated with the duct are the male prostate and accessory glands.

Human Mesonephric Duct position (week 6 to 11)
Mesonephric duct position week 6-11.jpg Schematic representations of the descent of the mesonephric duct (Wolffian duct, WD) or vas deferens. Anterior view.[6]


  • 6 weeks - (A) the WD opens to the urogenital sinus at a site adjacent to the ureteral orifice (UR).
  • 7–8 weeks - (B, C) rather than descent, there are individual variations in the WD position along the mediolateral axis as well as in left/right difference in morphology of the urogenital sinus (URS). The future bladder and urethra are not discriminated in the sinus.
  • 8–9 weeks - the bilateral upper angles (arrows) of the URS start upward growth toward the umbilicus.


  • 9 weeks - (D) depending on development of smooth muscles in the bladder as well as rhapdosphincter muscles of the urethra (RS), the descent of the vas deferens becomes evident. However, the epithelium is still same (arrowheads) between the future bladder and urethra.
  • 10–11 weeks - (E) a drastic upward growth of bladder smooth muscles as well as a developing prostate (PR) accelerates the descent of the vas.
Adult Ductus deferens
Testis histology 003.jpg
Adult Prostate
Prostate histology 01.jpg Prostate histology 02.jpg Prostate histology 03.jpg
Human prostate histology Corpora Amylacea Submucosal gland
(adult, low power overview) (adult, detail) (adult, high power detail)

External Genital

Historic diagram of external development (male left)
  • external genitalia are initially identical and undergo male and female differentiation under the influence or absence of steroidal sex hormones.
  • Indifferent stage ‐ cloaca divided by proliferating mesenchyme forming the urorectal septum which separates the ventral urogenital sinus from the dorsal rectum.
  • Difference stage ‐ locally in this region the presence or absence of dihydrotestosterone (DHT), generated from testosterone, determines male/female development.

Hormones

Anti-Müllerian Hormone

TGF-beta signaling pathway[7]

Anti-Müllerian Hormone (AMH, Müllerian Inhibiting Substance, MIS, Müllerian Inhibiting Factor, MIF) is a secreted glycoprotein factor of the transforming growth factor-beta, TGF-beta superfamily, that regulates gonadal and genital tract development. (Gene locus 19p13.3)

In the male embryo, the Sertoli cell secrete AMH and inhibit paramesonephric (Mullerian) duct development. This secreted hormone also acts to differentiate the Leydig cells (interstitial cells).

Ligand of TGF-beta (transforming growth factor-beta) superfamily and receptor binds to the anti-Mullerian hormone receptor type 2. Signalling pathway activate SMAD family transcription factors that regulate gene expression.

In postnatal males, AMH increases during the first month, reaching peak level at 6 months of age, and then slowly declines during childhood falling to low levels in puberty.


In reproductive age women, AMH is produced in the ovary by the granulosa cells surrounding preantral and small antral follicles and serum levels may reflect the remaining follicle cohort and decrease with age.

Sertoli cells release mainly a prohormone (proAMH), that is cleaved by subtilisin/kexin-type proprotein convertases or serine proteinases. The cleaved protein forms a stable complex (AMHN,C). Therefore the circulating AMH is a mixture of proAMH and AMHN,C. It has been suggested that proAMH may be activated within the gonads and also by its endocrine target-cells.


Preproprotein proteolytically processed to generate N- and C-terminal cleavage products, that homodimerize and associate to form a biologically active noncovalent complex. (see Protein Atlas)


Male testosterone and AMH level graph.jpg

Male testosterone and AMH levels

Ovary AMH

During ovary follicle development, the granulosa cells secrete AMH and it may have a role in follicular recruitment and development.[8] and may also function in postnatal elevation of FSH secretion in females.[9]

Other AMH Tissues

  • The placenta has also been shown to both synthesise AMH and express its receptors.[10]
  • AMH receptors have been identified in both the pituitary and brain.[9]


Links: TGF-beta | OMIM - AMH

Dihydrotestosterone (DHT)

Male presence of Dihydrotestosterone (DHT, 5α-dihydrotestosterone, androstanolone, 5α-androstan-17β-ol-3-one).
  • locally in this region leads to genital tubercle growth, form
  • genital folds (urethral) initial maintenance and then fusion, forming perineal and penile raphe.
  • labioscrotal swellings become the scrotum.
Testosterone metabolism


Links: Endocrinology - Diagram of the development of the external genitalia | image


Histology


Androgen and Digit ratio (2D:4D)

Androgen and Digit ratio (2D:4D

The ratio of 2nd and 4th finger (D, digit) length. This ratio has been suggested to relate to high fetal testosterone concentration (males have lower 2D:4D than females) and has been shown for several species.[11] Although a study in mice has not shown the same correlation.[12] There have been some suggestions that the ratio may also be an indicator of various neurological abnormalities.

To measure (2D:4D) - using your right hand palm up, measure the index finger (2) and ring finger (4) length from palm to tip. Dividing the index finger by the ring finger gives the 2D:4D ratio, average women ratio is 1, average men is 0.98.

Additional Images

References

  1. Gredler ML, Seifert AW & Cohn MJ. (2015). Tissue-specific roles of Fgfr2 in development of the external genitalia. Development , 142, 2203-12. PMID: 26081573 DOI.
  2. Ishiguro T, Tamagawa S & Ogawa H. (1992). [Changes of pupil size in brain death patients]. Seishin Shinkeigaku Zasshi , 94, 864-73. PMID: 1484906
  3. Funke S, Flach E, Kiss I, Sándor J, Vida G, Bódis J & Ertl T. (2010). Male reproductive tract abnormalities: more common after assisted reproduction?. Early Hum. Dev. , 86, 547-50. PMID: 20674196 DOI.
  4. Lin C, Yin Y, Veith GM, Fisher AV, Long F & Ma L. (2009). Temporal and spatial dissection of Shh signaling in genital tubercle development. Development , 136, 3959-67. PMID: 19906863 DOI.
  5. Wu X, Ferrara C, Shapiro E & Grishina I. (2009). Bmp7 expression and null phenotype in the urogenital system suggest a role in re-organization of the urethral epithelium. Gene Expr. Patterns , 9, 224-30. PMID: 19159697 DOI.
  6. Jin ZW, Abe H, Hinata N, Li XW, Murakami G & Rodríguez-Vázquez JF. (2016). Descent of mesonephric duct to the final position of the vas deferens in human embryo and fetus. Anat Cell Biol , 49, 231-240. PMID: 28127497 DOI.
  7. Pang K, Ryan JF, Baxevanis AD & Martindale MQ. (2011). Evolution of the TGF-β signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PLoS ONE , 6, e24152. PMID: 21931657 DOI.
  8. McLennan IS & Pankhurst MW. (2015). Anti-Müllerian hormone is a gonadal cytokine with two circulating forms and cryptic actions. J. Endocrinol. , 226, R45-57. PMID: 26163524 DOI.
  9. 9.0 9.1 Garrel G, Racine C, L'Hôte D, Denoyelle C, Guigon CJ, di Clemente N & Cohen-Tannoudji J. (2016). Anti-Müllerian hormone: a new actor of sexual dimorphism in pituitary gonadotrope activity before puberty. Sci Rep , 6, 23790. PMID: 27030385 DOI.
  10. Novembri R, Funghi L, Voltolini C, Belmonte G, Vannuccini S, Torricelli M & Petraglia F. (2015). Placenta expresses anti-Müllerian hormone and its receptor: Sex-related difference in fetal membranes. Placenta , 36, 731-7. PMID: 25972076 DOI.
  11. McIntyre MH. (2006). The use of digit ratios as markers for perinatal androgen action. Reprod. Biol. Endocrinol. , 4, 10. PMID: 16504142 DOI.
  12. Yan RH, Bunning M, Wahlsten D & Hurd PL. (2009). Digit ratio (2Dratio4D) differences between 20 strains of inbred mice. PLoS ONE , 4, e5801. PMID: 19495421 DOI.


Reviews

Cohn MJ. (2011). Development of the external genitalia: conserved and divergent mechanisms of appendage patterning. Dev. Dyn. , 240, 1108-15. PMID: 21465625 DOI.

Larney C, Bailey TL & Koopman P. (2014). Switching on sex: transcriptional regulation of the testis-determining gene Sry. Development , 141, 2195-205. PMID: 24866114 DOI.

Rey RA & Grinspon RP. (2011). Normal male sexual differentiation and aetiology of disorders of sex development. Best Pract. Res. Clin. Endocrinol. Metab. , 25, 221-38. PMID: 21397195 DOI.

Biason-Lauber A. (2010). Control of sex development. Best Pract. Res. Clin. Endocrinol. Metab. , 24, 163-86. PMID: 20541146 DOI.

Koopman P. (2010). The delicate balance between male and female sex determining pathways: potential for disruption of early steps in sexual development. Int. J. Androl. , 33, 252-8. PMID: 19845801 DOI.

Wilhelm D, Palmer S & Koopman P. (2007). Sex determination and gonadal development in mammals. Physiol. Rev. , 87, 1-28. PMID: 17237341 DOI.

Sharpe RM. (2006). Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract. Res. Clin. Endocrinol. Metab. , 20, 91-110. PMID: 16522522 DOI.

Warne GL & Kanumakala S. (2002). Molecular endocrinology of sex differentiation. Semin. Reprod. Med. , 20, 169-80. PMID: 12428197 DOI.

Adham IM, Emmen JM & Engel W. (2000). The role of the testicular factor INSL3 in establishing the gonadal position. Mol. Cell. Endocrinol. , 160, 11-6. PMID: 10715534

Hiort O & Holterhus PM. (2000). The molecular basis of male sexual differentiation. Eur. J. Endocrinol. , 142, 101-10. PMID: 10664515

Articles

Chawengsaksophak K, Svingen T, Ng ET, Epp T, Spiller CM, Clark C, Cooper H & Koopman P. (2012). Loss of Wnt5a disrupts primordial germ cell migration and male sexual development in mice. Biol. Reprod. , 86, 1-12. PMID: 21900680 DOI.

Cools M, Wolffenbuttel KP, Drop SL, Oosterhuis JW & Looijenga LH. (2011). Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex Dev , 5, 167-80. PMID: 21791949 DOI.


Search PubMed

Search Pubmed: Male Genital System Development | mesonephric duct

Terms

  • mesonephric duct - (Wollfian duct) An early developing urogenital paired duct system that initially runs the length of the embryo, that will differentiate and form the male reproductive duct system (ductus deferens). In females, this duct degenerates occasionally some remnants may remain associated in broad ligament.
  • Wolffian duct - (mesonephric duct, preferred terminology), A developmental duct that runs from the mesonephros to cloaca. The duct in male differentiates to form the ductus deferens and in female the same structure regresses. Historically named after Caspar Friedrich Wolff (1733-1794), a German scientist and early embryology researcher and is said to have established the doctrine of germ layers. (More? Caspar Friedrich Wolff)


Glossary Links

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Cite this page: Hill, M.A. (2018, June 22) Embryology Genital - Male Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Genital_-_Male_Development

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© Dr Mark Hill 2018, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G