Difference between revisions of "Testis Development"

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Postnatally in humans, at 2 months of age, primordial germ cells (gonocytes) are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) population that at puberty will commence differentiation into spermatozoa. Postnatally, fetal Leydig cells are also replaced by adult cells. Development of the testis is driven at puberty by the endocrine HPG axis:
 
Postnatally in humans, at 2 months of age, primordial germ cells (gonocytes) are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) population that at puberty will commence differentiation into spermatozoa. Postnatally, fetal Leydig cells are also replaced by adult cells. Development of the testis is driven at puberty by the endocrine HPG axis:
# Hypothalamus - gonadotropin-releasing hormone (GnRH)
+
# {{hypothalamus}} - gonadotropin-releasing hormone (GnRH)
# Pituitary - gonadotropins, leutenising hormone (LH) and follicle stimulating hormone (FSH)
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# {{pituitary}} - gonadotropins, leutenising hormone (LH) and follicle stimulating hormone (FSH)
# Gonad - testosterone
+
# Gonad ({{testis}}) - {{testosterone}}
 +
<br>
 +
{{Seminiferous Tubule puberty table}}
 +
<br>
 +
:'''Links:''' {{Sertoli cell}} | {{Leydig cell}}
  
{{Seminiferous Tubule puberty table}}
 
 
<br>
 
<br>
 
{{Genital Links}}
 
{{Genital Links}}
 
==Some Recent Findings==
 
==Some Recent Findings==
 +
[[File:Model male androsterone synthesis.jpg|alt=Model male second trimester androsterone synthesis|thumb|Model male second trimester androsterone synthesis{{#pmid:30763313|PMID30763313}}]]
 
[[File:Gadd45g and sex determination model.jpg|thumb|link=#Gadd45g|Gadd45g and Sex Determination Model{{#pmid:23516551|PMID23516551}}]]
 
[[File:Gadd45g and sex determination model.jpg|thumb|link=#Gadd45g|Gadd45g and Sex Determination Model{{#pmid:23516551|PMID23516551}}]]
 
{|
 
{|
 
|-bgcolor="F5FAFF"  
 
|-bgcolor="F5FAFF"  
 
|
 
|
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* '''XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage'''{{#pmid:30289439|PMID30289439}} "The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry- mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry- females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry- PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry- oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as "Swyer syndrome," in which patients with an XY karyotype present as typical females and are infertile."
  
* '''Sertoli Cell Wt1 Regulates Peritubular Myoid Cell and Fetal Leydig Cell Differentiation during Fetal Testis Development'''{{#pmid:28036337|PMID28036337}} "Sertoli cells play a significant role in regulating fetal testis compartmentalization to generate testis cords and interstitium during development. The Sertoli cell Wilms' tumor 1 (Wt1) gene, which encodes ~24 zinc finger-containing transcription factors, is known to play a crucial role in fetal testis cord assembly and maintenance. ... In summary, Wt1 regulates the development of FLC and interstitial progenitor cell lineages through Notch signaling, and it also plays a role in PMC development. Collectively, these effects confer fetal testis compartmentalization. See also - Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis PMID 24803659
+
* '''Review - Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEA-S) in Mammalian Reproduction'''{{#pmid:30029728|PMID30029728}} "Steroid hormones form an integral part of normal development in mammalian organisms. Cholesterol is the parent compound from which all steroid hormones are synthesized. The product pregnenolone formed from cholesterol serves as precursor for mineralocorticoids, glucocorticoids, as well as dehydroepiandrosterone (DHEA) and its derived sexual hormones. DHEA assumes the prohormone status of a predominant endogenous precursor and a metabolic intermediate in ovarian follicular steroidogenesis. DHEA supplementation has been used to enhance ovarian reserve. Steroids like estradiol and testosterone have long been contemplated to play important roles in regulating meiotic maturation of oocytes in conjunction with gonadotropins. It is known that oocyte priming with estrogen is necessary to develop calcium (Ca2+) oscillations during maturation. Accruing evidence from diverse studies suggests that DHEA and its sulfate (dehydroepiandrosterone sulfate, DHEA-S) play significantly vital role not only as intermediates in androgen and estrogen formation, but may also be the probable 'oocyte factor' and behave as endogenous agonists triggering calcium oscillations for oocyte activation. DHEA/DHEA-S have been reported to regulate calcium channels for the passage of Ca2+ through the oocyte cytoplasm and for maintaining required threshold of Ca2+ oscillations. This role of DHEA/DHEA-S assumes critical significance in assisted reproductive technology and in-vitro fertilization treatment cycles where physical, chemical, and mechanical methods are employed for artificial oocyte activation to enhance fertilization rates."
 
 
* '''R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis'''{{#pmid:25910078|PMID25910078}} "Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1."
 
 
 
* '''Gadd45g is essential for primary sex determination, male fertility and testis development'''{{#pmid:23516551|PMID23516551}}  "In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex differentiation. ...The molecular cause of the sex reversal was the failure of Gadd45g(-/-) XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans."
 
  
 +
* '''Reciprocal Spatiotemporally Controlled {{Apoptosis}} Regulates Wolffian Duct Cloaca Fusion'''{{#pmid:29326158|PMID29326158}} "The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT."  {{Apoptosis}}
 
|}
 
|}
 
{| class="wikitable mw-collapsible mw-collapsed"
 
{| class="wikitable mw-collapsible mw-collapsed"
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| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}
 
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}
  
Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Testis+Embryology ''Testis Embryology'']
+
Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Testis+Embryology ''Testis Embryology''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Testis+Development ''Testis Development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Spermatogenesis ''Spermatogenesis''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Leydig+Cell+Development ''Leydig Cell Development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Sertoli+Cell+Development ''Sertoli Cell Development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Spermatogonia ''Spermatogonia''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Endocrine+Testis ''Endocrine Testis''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Testis+Descent ''Testis Descent''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Gubernaculum ''Gubernaculum''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Azoospermia ''Azoospermia''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Anorchia ''Anorchia''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cryptorchidism ''Cryptorchidism''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Hydrocele ''Hydrocele'']
 
 
<pubmed limit=5>Testis Embryology</pubmed>
 
 
|}
 
|}
 
{| class="wikitable mw-collapsible mw-collapsed"
 
{| class="wikitable mw-collapsible mw-collapsed"
 
! Older papers &nbsp;
 
! Older papers &nbsp;
 
|-
 
|-
|  
+
| {{Older papers}}
 +
* '''Sertoli Cell Wt1 Regulates Peritubular Myoid Cell and Fetal Leydig Cell Differentiation during Fetal Testis Development'''{{#pmid:28036337|PMID28036337}} "Sertoli cells play a significant role in regulating fetal testis compartmentalization to generate testis cords and interstitium during development. The Sertoli cell Wilms' tumor 1 (Wt1) gene, which encodes ~24 zinc finger-containing transcription factors, is known to play a crucial role in fetal testis cord assembly and maintenance. ... In summary, Wt1 regulates the development of FLC and interstitial progenitor cell lineages through Notch signaling, and it also plays a role in PMC development. Collectively, these effects confer fetal testis compartmentalization. See also - Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis PMID 24803659
 +
 
 +
* '''R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis'''{{#pmid:25910078|PMID25910078}} "Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1."
 +
 
 +
* '''Gadd45g is essential for primary sex determination, male fertility and testis development'''{{#pmid:23516551|PMID23516551}}  "In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex differentiation. ...The molecular cause of the sex reversal was the failure of Gadd45g(-/-) XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans."
 +
 
 
* '''Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testes development''' {{#pmid:21493716|PMID21493716}}  "Androgens play important roles during the first trimester of intrauterine life, coinciding with genital tract differentiation, during virilization and maintenance of secondary male characteristics and during initiation of spermatogenesis. ... Findings from this study demonstrate that exposure to excess testosterone/5α-dihydrotestosterone (DHT) during male fetal sexual differentiation have differential effects on post-pubertal testicular size, seminiferous tubule size and function, sperm motility, and testosterone concentrations." {{sheep}}
 
* '''Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testes development''' {{#pmid:21493716|PMID21493716}}  "Androgens play important roles during the first trimester of intrauterine life, coinciding with genital tract differentiation, during virilization and maintenance of secondary male characteristics and during initiation of spermatogenesis. ... Findings from this study demonstrate that exposure to excess testosterone/5α-dihydrotestosterone (DHT) during male fetal sexual differentiation have differential effects on post-pubertal testicular size, seminiferous tubule size and function, sperm motility, and testosterone concentrations." {{sheep}}
  
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{{Testis stage22}}
 
{{Testis stage22}}
  
 +
<div id="Sertoli cell"></div>
 
==Sertoli Cells==
 
==Sertoli Cells==
  
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* Transforming Growth Factor-beta (TGFbeta)
 
* Transforming Growth Factor-beta (TGFbeta)
  
 +
 +
:'''Links:''' {{Sertoli cell}}
 +
 +
<div id="Leydig cell"></div>
 
==Leydig Cells==
 
==Leydig Cells==
 
[[File:Testis_histology_2.jpg|thumb|Seminiferous tubule cross-section and supporting cells]]
 
[[File:Testis_histology_2.jpg|thumb|Seminiferous tubule cross-section and supporting cells]]
Interstitial or {{Leydig cells}}, named after German zoologist Franz von Leydig (1821 - 1908) who first histologically described them in 1850.<ref name=Leydig1850>''Zur Anatomie der männlichen Geschlechtsorgane und Analdrüsen der Säugetiere'' (On the anatomy of the male sexual organs and anal glands of the mammals). (1850) Zeitschr. f. wiss. Zoologie.</ref> Their initial development appears to be influenced by Sertoli cell differentiation.
+
Interstitial or {{Leydig cell}}, named after German zoologist Franz von Leydig (1821 - 1908) who first histologically described them in 1850.<ref name=Leydig1850>''Zur Anatomie der männlichen Geschlechtsorgane und Analdrüsen der Säugetiere'' (On the anatomy of the male sexual organs and anal glands of the mammals). (1850) Zeitschr. f. wiss. Zoologie.</ref> Their initial development appears to be influenced by Sertoli cell differentiation.
  
 
These cells produce the male testicular androgens and have a role during life prenatally (fetal) and postnatally during puberty onward.
 
These cells produce the male testicular androgens and have a role during life prenatally (fetal) and postnatally during puberty onward.
  
Potential origin of {{Leydig cells}}{{#pmid:219339813|PMID219339813}} - {{neural crest}}, coelomic epithelium (mesothelium), mesonephros or unknown. In the mouse both fetal and adult Leydig cells appear to arise from a common progenitor population.{{#pmid:27940302|PMID27940302}}
+
Fetal Leydig cells develop from coelomic epithelium and undifferentiated perivascular cells in the gonad–mesonephros border region.
 +
 
 +
Adult Leydig cells appear after birth from stem/progenitor cells  among peritubular and peri-vascular cells.  
 +
 
 +
In the mouse both fetal and adult Leydig cells appear to arise from a common progenitor population.{{#pmid:27940302|PMID27940302}}
  
  
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Fetal Leydig Cells produce androstenedione but lack 17β-hydroxysteroid dehydrogenase (17β-HSD), to but produce  testosterone. Fetal Sertoli cells do express 17β-HSD and can therefore convert androstenedione to testosterone.{{#pmid:26968934|PMID26968934}}
 
Fetal Leydig Cells produce androstenedione but lack 17β-hydroxysteroid dehydrogenase (17β-HSD), to but produce  testosterone. Fetal Sertoli cells do express 17β-HSD and can therefore convert androstenedione to testosterone.{{#pmid:26968934|PMID26968934}}
  
(More? {{pituitary}})
+
:'''Links:''' {{pituitary}}
  
 
===Adult Leydig Cells===
 
===Adult Leydig Cells===
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|}
 
|}
 
EM images above from historic study of the opossum testis.{{#pmid:13693345|PMID13693345}}
 
EM images above from historic study of the opossum testis.{{#pmid:13693345|PMID13693345}}
 +
<br>
 +
===Testosterone===
 +
Leydig cells produce testosterone. Historically in 1935, Ernst Laqueur (Amsterdam, Netherlands) isolated testosterone, and Adolf Butenandt (Gdansk. Poland) and Leopold Ruzicka (Zürich, Switzerland) synthesised testosterone.{{#pmid:30959485|PMID30959485}}
 +
 +
{|
 +
| [[File:Model male androsterone synthesis.jpg|500px]]
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| Proposed steroidogenic pathways leading to androsterone synthesis and masculinization in the second trimester human male fetus.{{#pmid:30763313|PMID30763313}}
 +
 +
Steroid hormone conversion is shown by wide green arrows, with the converting enzymes written within the arrow. Red arrows show potential transport between organs in the fetal circulation. The blue double-headed arrow indicates that exchange is also taking place between the placenta and the maternal circulation. Most circulating progesterone in the fetal circulation is likely to come from the placenta, and this will be reduced to 5αDHP by SRD5A1 in the placenta, fetal liver, and fetal testis, with the fetal liver likely to be the major site. Allopregnanolone (AlloP5) production by AKR1C2 is also most likely to occur in the placenta and fetal liver because the substrate is present in those tissues, and they express the highest total levels of enzyme transcript. Some conversion may also occur in the testis. Significant levels of androsterone are only detectable in the placenta and adrenal, and thus they are a likely source of the circulating steroid, although, given sex differences, other tissues are probably involved. The adrenal lacks other intermediates in the backdoor pathway, and thus AlloP5 must come from other tissues.
 +
 +
The placenta lacks CYP17A1, so androsterone production is likely to depend on adrenal DHEA as substrate. Testosterone from the fetal testes also acts as an essential substrate for DHT synthesis at the external genitalia.
 +
 +
AlloP5, allopregnanolone; An, androsterone; DHEA, dehydroepiandrosterone; DHT, 5α-dihydrotestosterone; P4, progesterone; P5, pregnenolone; T, testosterone; 5αDHP, 5α-dihydroprogesterone.
 +
|}
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The adult testes produce about 6-10 mg /day in males (~0.5 mg / day in females) carried in circulation by a specific carrier globulin.
 +
 
==Peritubular Myoid Cells==
 
==Peritubular Myoid Cells==
 
The {{peritubular myoid cell}} surrounds the seminiferous tubule and have smooth muscle properties. Contraction of theses cells aids spermatozoa movement within the seminiferous tubule towards the epididymis for storage.  
 
The {{peritubular myoid cell}} surrounds the seminiferous tubule and have smooth muscle properties. Contraction of theses cells aids spermatozoa movement within the seminiferous tubule towards the epididymis for storage.  
  
 +
 +
==Tunica Albuginea==
 +
The capsule surrounding the testis is a multilayered fibrous structure. The main component of the capsule is the tunica albuginea composed dense collagen fibres, fibroblasts and smooth muscle cells.
  
 
==Epididymis ==
 
==Epididymis ==
 +
[[File:Testis histology 02.jpg|alt=testis histology|thumb|Human testis showing the epididymis (right)]]
 
[[File:Testis_histology_008.jpg|thumb|Adult Epididymis Histology]]
 
[[File:Testis_histology_008.jpg|thumb|Adult Epididymis Histology]]
[[File:Mouse epididymis development 01.jpg|thumb|Mouse postnatal epididymis development{{#pmid:22701646|PMID22701646}}]]
 
 
Both the ductus epididymis and ductus deferens differentiate from the mesonephric duct (Wollfian duct) elongation (cell proliferation). In the case of the epididymis, elongation also is associated with extensive coiling, the adult human epididymis about 6 metres in length (mouse 1m, rat 3m). Embryonic growth is regulated by androgens, members of the PCP pathway, and inhibin beta A. While postnatally androgens and other growth factors may have roles in final maturation. (see review{{#pmid:21441421|PMID21441421}}) The ductus epididymis is lined by a very tall pseudostratified columnar epithelium, consisting of principal cells with long stereo cilia.
 
Both the ductus epididymis and ductus deferens differentiate from the mesonephric duct (Wollfian duct) elongation (cell proliferation). In the case of the epididymis, elongation also is associated with extensive coiling, the adult human epididymis about 6 metres in length (mouse 1m, rat 3m). Embryonic growth is regulated by androgens, members of the PCP pathway, and inhibin beta A. While postnatally androgens and other growth factors may have roles in final maturation. (see review{{#pmid:21441421|PMID21441421}}) The ductus epididymis is lined by a very tall pseudostratified columnar epithelium, consisting of principal cells with long stereo cilia.
  
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* '''terminal segment''' - site of storage of the mature spermatozoa.  
 
* '''terminal segment''' - site of storage of the mature spermatozoa.  
  
Anatomically the adult epididymis consists of 3 regions:
+
{|
* '''body''' or central portion.
+
| [[File:Nelsen1953 fig007.jpg|300px]]
* '''head''' (globus major) upper enlarged extremity.
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| Anatomically the adult epididymis is about 30 cm in length and consists of 3 regions:
* '''tail''' (globus minor) lower pointed extremity, continuous with the ductus deferens (vas deferens).  
+
* '''Caput''' (head, globus major) upper enlarged extremity, consisting of a few tubes interconnecting at three levels.
 +
* '''Corpus''' (body, or central portion).
 +
* '''Cauda''' (tail, globus minor) lower pointed extremity, continuous with the ductus deferens (vas deferens).  
 +
|}
  
 
The head is intimately connected with the upper end of the testis by means of the efferent ductules of the gland; the tail is connected with the lower end by cellular tissue, and a reflection of the tunica vaginalis (tunica vaginalis propria testis) the serous covering of the testis.
 
The head is intimately connected with the upper end of the testis by means of the efferent ductules of the gland; the tail is connected with the lower end by cellular tissue, and a reflection of the tunica vaginalis (tunica vaginalis propria testis) the serous covering of the testis.
  
 
The lateral surface, head and tail of the epididymis are free and covered by the serous membrane; the body is also completely invested by it, excepting along its posterior border; while between the body and the testis is a pouch, named the sinus of the epididymis (digital fossa). The epididymis is connected to the back of the testis by a fold of the serous membrane.
 
The lateral surface, head and tail of the epididymis are free and covered by the serous membrane; the body is also completely invested by it, excepting along its posterior border; while between the body and the testis is a pouch, named the sinus of the epididymis (digital fossa). The epididymis is connected to the back of the testis by a fold of the serous membrane.
 +
 +
===Caput===
 +
In humans, the majority of the caput (head, globus major) is primarily efferent ducts and not epididymal duct, with multiple efferent ducts connecting to the main epididymal duct.{{#pmid:7873793|PMID7873793}}
 +
 +
[[File:Mouse epididymis development 01.jpg|thumb|Mouse postnatal epididymis development{{#pmid:22701646|PMID22701646}}]]
 +
'''Adult Mouse Epididymis Histology'''{{#pmid:19758979|PMID19758979}}
 +
 +
[[File:Mouse- epididymis histology.jpg|500px]]
  
 
==Testis Descent==
 
==Testis Descent==
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The regulation of testis descent is still being investigated and several different factors have been identified that may have roles in descent. The first stage of testicular descent occurs 10–15 weeks of gestation with the testes moving to the inguinal region. The second inguino-scrotal phase occurs between 25-35 weeks.{{#pmid:27286121|PMID27286121}}
 
The regulation of testis descent is still being investigated and several different factors have been identified that may have roles in descent. The first stage of testicular descent occurs 10–15 weeks of gestation with the testes moving to the inguinal region. The second inguino-scrotal phase occurs between 25-35 weeks.{{#pmid:27286121|PMID27286121}}
  
The gubernaculum (gubernaculum Hunteri) is the caudal inguinoscrotal ligament that connects the testis to the lower abdomen. The cranial suspensory ligament (mesonephric ligament) is the cranial ligament that connects the tesitis to the posterior abdominal wall.
+
===Gubernaculum===
 +
 
 +
The {{gubernaculum}} (''gubernaculum Hunteri'') is the caudal inguinoscrotal ligament that connects the testis to the lower abdomen. The cranial suspensory ligament (mesonephric ligament) is the cranial ligament that connects the tesitis to the posterior abdominal wall.
  
 
* Insulin-like factor 3 (INSL3, relaxin-like factor) from fetal leydig cells acting through its receptor (Rxfp2) and BMP and WNT signaling pathways to promote testis descent.
 
* Insulin-like factor 3 (INSL3, relaxin-like factor) from fetal leydig cells acting through its receptor (Rxfp2) and BMP and WNT signaling pathways to promote testis descent.
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:'''Links:''' [http://www.ncbi.nlm.nih.gov/omim/146738 OMIM - INSL3]
+
:'''Links:''' [http://www.ncbi.nlm.nih.gov/pubmed/?term=Gubernaculum Search PubMed ''Gubernaculum'']| [http://www.ncbi.nlm.nih.gov/omim/146738 OMIM - INSL3]
  
 
==Puberty==
 
==Puberty==
 
 
[[File:Male_testosterone_and_AMH_level_graph.jpg|600px]]
 
[[File:Male_testosterone_and_AMH_level_graph.jpg|600px]]
  
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In humans at puberty, hormonal and morphological changes occur within the gonad and other systems (secondary sex characteristics). Within the testis the immature Sertoli cells cease to proliferate and differentiate. Spermatogonium proliferate and spermatogenesis begins, and it takes about 70 days for cells to mature from the diploid spermatogonium to a primary spermatocyte. This maturation occurs in waves along the seminiferous tubules.
 
In humans at puberty, hormonal and morphological changes occur within the gonad and other systems (secondary sex characteristics). Within the testis the immature Sertoli cells cease to proliferate and differentiate. Spermatogonium proliferate and spermatogenesis begins, and it takes about 70 days for cells to mature from the diploid spermatogonium to a primary spermatocyte. This maturation occurs in waves along the seminiferous tubules.
  
'''Links:''' [[Puberty Development]]
 
  
 +
[[File:Male puberty testicular volume graph.jpg|alt=Male puberty testicular volume graph|600px]]
 
[[File:Orchidometer.jpg|thumb|alt=orchidometer|orchidometer]]
 
[[File:Orchidometer.jpg|thumb|alt=orchidometer|orchidometer]]
 +
Male puberty testicular volume graph{{#pmid:22682237|PMID22682237}}
 +
 +
Testicular volume increase at puberty can be measured by: including orchidometry, rulers, calipers, and ultrasonography. There is also an earlier empirical formula developed by Lambert{{#pmid:15444009|PMID15444009}} used to estimate testicular volume.
 +
 +
 +
'''Links:''' {{Puberty}}
 +
 
===Orchidometer===
 
===Orchidometer===
  
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==Blood-Testis Barrier ==
 
==Blood-Testis Barrier ==
 +
[[File:Rat blood–testis barrier 02.jpg|thumb|alt=Rat blood–testis barrier|Rat blood–testis barrier{{#pmid:17698604|PMID17698604}}]]
  
 
Within the testis seminiferous tubules the Sertoli cells located near the basement membrane act as an initial cellular barrier with many functions, but often described as forming a "blood-testis barrier". (see review{{#pmid:21134990|PMID21134990}}
 
Within the testis seminiferous tubules the Sertoli cells located near the basement membrane act as an initial cellular barrier with many functions, but often described as forming a "blood-testis barrier". (see review{{#pmid:21134990|PMID21134990}}
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* establish a basal and adluminal (apical) compartment (specialized microenvironment)
 
* establish a basal and adluminal (apical) compartment (specialized microenvironment)
 
* provide an immunological privilege status of the testis (anti-sperm antibodies are not developed)
 
* provide an immunological privilege status of the testis (anti-sperm antibodies are not developed)
 +
 +
{|
 +
! Tight Junctions
 +
! Adherens Junctions
 +
|-
 +
| [[File:Tight junction 01.jpg|alt=tight junctions|200px]]
 +
| [[File:Adherens Junction 01.jpg|alt=adherens junctions|200px]]
 +
|-
 +
| Germ cells first have to break through the tight junctions at the BTB with minimal disruptions.
 +
| Progression of germ cells then relies on series of transient adherens junctions at the Sertoli–germ cell interface.
 +
|-
 +
| colspan=2|Assembly and disassembly of junctional complexes at the basal and apical ectoplasmic specialization occurs continuously.
 +
|}
 +
 +
<br>
  
 
==Abnormalities==
 
==Abnormalities==
 +
===Male Infertility Genes===
 +
 +
{{Male Infertility Genes table 1}}
 +
 +
===International Classification of Diseases===
 +
{{ICD-11 Testis anomalies table}}
 +
 
===Cryptorchidism===
 
===Cryptorchidism===
[[File:Cryptorchidism.jpg|thumb|Cryptorchidism]]
+
[[File:Cryptorchidism.jpg|thumb|{{Cryptorchidism}}]]
 +
{|
 +
|-bgcolor="FEF9E7"
 +
| {{ICD-11}} {{ICD11weblink}}1134950387 LB52 Cryptorchidism] - ''A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by the absence of one or both testes from the scrotum. This disorder may also present with reduced fertility, psychological implications, or increased risk of testicular germ cell tumours. Confirmation is by imaging, karyotyping, or identification of male sex hormones in a blood sample.''
 +
|}
 
[[File:Newborn- cryptorchidism normal birthweight.jpg|thumb|Newborn - cryptorchidism normal birthweight{{#pmid:18032558|PMID18032558}}]]
 
[[File:Newborn- cryptorchidism normal birthweight.jpg|thumb|Newborn - cryptorchidism normal birthweight{{#pmid:18032558|PMID18032558}}]]
 
The external location of the testes in the scrotum acts as a local thermo-regulator and provides a temperature environment below that of the general body temperature.{{#pmid:17839834|PMID17839834}} This thermal function is essential for normal spermatogenesis and cryptorchidism therefore affects fertility.
 
The external location of the testes in the scrotum acts as a local thermo-regulator and provides a temperature environment below that of the general body temperature.{{#pmid:17839834|PMID17839834}} This thermal function is essential for normal spermatogenesis and cryptorchidism therefore affects fertility.
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Management of cryptorchidism in children: guidelines.{{#pmid:18726735|PMID18726735}} "Cryptorchidism is best diagnosed clinically, and treated by surgical orchiopexy at age 6-12 months, without a routine biopsy. If no testis is palpable, or if other signs of hypovirilisation such as hypospadias are present, the chromosomal sex and hormonal status must be assessed. Laparoscopy is the best way of diagnosing and managing intra-abdominal testes."
 
Management of cryptorchidism in children: guidelines.{{#pmid:18726735|PMID18726735}} "Cryptorchidism is best diagnosed clinically, and treated by surgical orchiopexy at age 6-12 months, without a routine biopsy. If no testis is palpable, or if other signs of hypovirilisation such as hypospadias are present, the chromosomal sex and hormonal status must be assessed. Laparoscopy is the best way of diagnosing and managing intra-abdominal testes."
  
 +
:'''Links:''' {{Cryptorchidism}}
 
===Anorchia===
 
===Anorchia===
 +
{|
 +
|-bgcolor="FEF9E7"
 +
| {{ICD-11}} {{ICD11weblink}}997805288 LB51 Anorchia or microorchidia] - ''A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by individuals who are born with absence of the testes, or with testes that are deficient in size and function. Confirmation is by physical examination, identification of low testosterone levels but elevated follicle stimulating hormone and luteinizing hormone levels in a blood sample, or imaging.''
 +
|}
 
Clinical term for (embryonic testicular regression, vanishing testis syndrome) the absence of testes in a 46,XY individual with a male phenotype. Rare abnormality with an incidence of about 1 in 20,000 male births, and occurs more frequently with cryptorchidism (1 in 177 cases).  
 
Clinical term for (embryonic testicular regression, vanishing testis syndrome) the absence of testes in a 46,XY individual with a male phenotype. Rare abnormality with an incidence of about 1 in 20,000 male births, and occurs more frequently with cryptorchidism (1 in 177 cases).  
  
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===Sox9===
 
===Sox9===
 +
Recent studies have identified upstream SOX9 enhancers that when duplicated or deleted result in 46,XX or 46,XY sex reversal, respectively.{{#pmid:29903884|PMID29903884}}{{#pmid:30552336|PMID30552336}}
 +
 +
 
* autosomal transcription factor
 
* autosomal transcription factor
 
* Development of XY females - presence of only a single functional copy of the transcription factor encoding genes SOX9, SF1, or WT1 (Note- not all XY humans are sex-reversed if only a single copy of a normal SF1 or WT1 allele is present)
 
* Development of XY females - presence of only a single functional copy of the transcription factor encoding genes SOX9, SF1, or WT1 (Note- not all XY humans are sex-reversed if only a single copy of a normal SF1 or WT1 allele is present)
Line 333: Line 423:
  
  
:'''Links:'''  [http://www.ncbi.nlm.nih.gov/omim/608160 Sox9] | [[Musculoskeletal_System_-_Cartilage_Development|Cartilage Development]] | [[Hearing_-_Inner_Ear_Development|Inner Ear Development]]
+
:'''Links:'''  [http://www.ncbi.nlm.nih.gov/omim/608160 OMIM Sox9] | {{Cartilage}} | {{Inner ear}}
  
 
===Fog2===
 
===Fog2===
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===Reviews===
 
===Reviews===
 +
{{#pmid:31033257}}
 +
 +
{{#pmid:30999282}}
 +
 +
{{#pmid:30902461}}
 +
 
{{#pmid:29771299}}
 
{{#pmid:29771299}}
 +
 +
{{#pmid:29371022}}
  
 
{{#pmid:27484857}}
 
{{#pmid:27484857}}
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{{#pmid:19339813}}
 
{{#pmid:19339813}}
 
===Articles===
 
===Articles===
 +
{{#pmid:29807571}}
 +
 
{{#pmid:21147849}}
 
{{#pmid:21147849}}
  

Latest revision as of 15:46, 7 June 2019

Embryology - 17 Sep 2019    Facebook link Pinterest link Twitter link  Expand to Translate  
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العربية | català | 中文 | 中國傳統的 | français | Deutsche | עִברִית | हिंदी | bahasa Indonesia | italiano | 日本語 | 한국어 | မြန်မာ | Pilipino | Polskie | português | ਪੰਜਾਬੀ ਦੇ | Română | русский | Español | Swahili | Svensk | ไทย | Türkçe | اردو | ייִדיש | Tiếng Việt    These external translations are automated and may not be accurate. (More? About Translations)

Introduction

Historic testis drawing

The male gonad is the testis (pl, testes).

The initial difference in male and female gonad development are dependent on testis-determining factor (TDF) the protein product of the Y chromosome SRY gene. Recent studies have indicated that additional factors may also be required for full differentiation. The seminiferous tubules are considered the parenchyma of the testis. Within the developing testis the three main differentiating cell types are: gamete forming cells (spermatogonia), support cells (Sertoli cells) and hormone secreting cells (Leydig or interstitial cells).


Postnatally in humans, at 2 months of age, primordial germ cells (gonocytes) are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) population that at puberty will commence differentiation into spermatozoa. Postnatally, fetal Leydig cells are also replaced by adult cells. Development of the testis is driven at puberty by the endocrine HPG axis:

  1. hypothalamus‎ - gonadotropin-releasing hormone (GnRH)
  2. pituitary - gonadotropins, leutenising hormone (LH) and follicle stimulating hormone (FSH)
  3. Gonad (testis) - testosterone


Testis - Seminiferous Tubule
Pre-puberty Post-puberty
Testis histology 006.jpg Testis histology 011.jpg
Cross-sectional view of the seminiferous tubule histology before and after puberty.


Links: sertoli cell | Leydig cell


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 
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

Model male second trimester androsterone synthesis
Model male second trimester androsterone synthesis[1]
Gadd45g and Sex Determination Model[2]
  • XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage[3] "The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry- mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry- females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry- PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry- oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as "Swyer syndrome," in which patients with an XY karyotype present as typical females and are infertile."
  • Review - Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEA-S) in Mammalian Reproduction[4] "Steroid hormones form an integral part of normal development in mammalian organisms. Cholesterol is the parent compound from which all steroid hormones are synthesized. The product pregnenolone formed from cholesterol serves as precursor for mineralocorticoids, glucocorticoids, as well as dehydroepiandrosterone (DHEA) and its derived sexual hormones. DHEA assumes the prohormone status of a predominant endogenous precursor and a metabolic intermediate in ovarian follicular steroidogenesis. DHEA supplementation has been used to enhance ovarian reserve. Steroids like estradiol and testosterone have long been contemplated to play important roles in regulating meiotic maturation of oocytes in conjunction with gonadotropins. It is known that oocyte priming with estrogen is necessary to develop calcium (Ca2+) oscillations during maturation. Accruing evidence from diverse studies suggests that DHEA and its sulfate (dehydroepiandrosterone sulfate, DHEA-S) play significantly vital role not only as intermediates in androgen and estrogen formation, but may also be the probable 'oocyte factor' and behave as endogenous agonists triggering calcium oscillations for oocyte activation. DHEA/DHEA-S have been reported to regulate calcium channels for the passage of Ca2+ through the oocyte cytoplasm and for maintaining required threshold of Ca2+ oscillations. This role of DHEA/DHEA-S assumes critical significance in assisted reproductive technology and in-vitro fertilization treatment cycles where physical, chemical, and mechanical methods are employed for artificial oocyte activation to enhance fertilization rates."
  • Reciprocal Spatiotemporally Controlled apoptosis Regulates Wolffian Duct Cloaca Fusion[5] "The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT." apoptosis
More recent papers  
Mark Hill.jpg
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This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.

  • This search now requires a manual link as the original PubMed extension has been disabled.
  • The displayed list of references do not reflect any editorial selection of material based on content or relevance.
  • References also appear on 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.

More? References | Discussion Page | Journal Searches | 2019 References

Search term: Testis Embryology | Testis Development | Spermatogenesis | Leydig Cell Development | Sertoli Cell Development | Spermatogonia | Endocrine Testis | Testis Descent | Gubernaculum | Azoospermia | Anorchia | Cryptorchidism | Hydrocele

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Sertoli Cell Wt1 Regulates Peritubular Myoid Cell and Fetal Leydig Cell Differentiation during Fetal Testis Development[6] "Sertoli cells play a significant role in regulating fetal testis compartmentalization to generate testis cords and interstitium during development. The Sertoli cell Wilms' tumor 1 (Wt1) gene, which encodes ~24 zinc finger-containing transcription factors, is known to play a crucial role in fetal testis cord assembly and maintenance. ... In summary, Wt1 regulates the development of FLC and interstitial progenitor cell lineages through Notch signaling, and it also plays a role in PMC development. Collectively, these effects confer fetal testis compartmentalization. See also - Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis PMID 24803659
  • R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis[7] "Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1."
  • Gadd45g is essential for primary sex determination, male fertility and testis development[2] "In humans and most mammals, differentiation of the embryonic gonad into ovaries or testes is controlled by the Y-linked gene SRY. Here we show a role for the Gadd45g protein in this primary sex differentiation. ...The molecular cause of the sex reversal was the failure of Gadd45g(-/-) XY gonads to achieve the SRY expression threshold necessary for testes differentiation, resulting in ovary and Müllerian duct development. These results identify Gadd45g as a candidate gene for male infertility and 46,XY sex reversal in humans."
  • Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testes development [8] "Androgens play important roles during the first trimester of intrauterine life, coinciding with genital tract differentiation, during virilization and maintenance of secondary male characteristics and during initiation of spermatogenesis. ... Findings from this study demonstrate that exposure to excess testosterone/5α-dihydrotestosterone (DHT) during male fetal sexual differentiation have differential effects on post-pubertal testicular size, seminiferous tubule size and function, sperm motility, and testosterone concentrations." sheep
  • Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal.[9] "We have uncovered a mechanism by which oestrogen can regulate gonadal development through the nucleocytoplasmic shuttling of SOX9. This may represent an underlying ancestral mechanism by which oestrogen promotes ovarian development in the gonads of nonmammalian vertebrates. Furthermore, oestrogen may retain this function in adult female mammals to maintain granulosa cell fate in the differentiated ovary by suppressing nuclear translocation of the SOX9 protein."
  • The evolutionary history of testicular externalization and the origin of the scrotum[10] "We mapped four character states reflecting the position of testes and presence of scrotum onto recent mammalian phylogeny. Our results are interpreted as follows: as to the presence of testicondy in Monotremata and most of Atlantogenata, which represent the basal group of all eutherians, we argue that primary testicondy represents a plesiomorphic condition for Eutheria as well as for all mammals. This is in opposition to the previous hypothesis of Werdelin and Nilsonne that the scrotum may have evolved before the origin of mammals and then repeatedly disappeared in many groups including monotremes. We suggest that the scrotum evolved at least twice during the evolutionary history of mammals, within Marsupialia and Boreoeutheria, and has subsequently been lost by many groups; this trend is especially strong in Laurasiatheria. We suggest that the recent diversity in testicular position within mammals is the result of multiple selection pressures stemming from the need to provide conditions suitable for sperm development and storage, or to protect the male gonads from excessive physical and physiological disturbance."
  • FGF signaling directs a center-to-pole expansion of tubulogenesis in mouse testis differentiation.[11] "These observations imply that center-to-pole FGF9 diffusion directs a poleward expansion of testiculogenic programs along the anteroposterior axis of developing XY gonads."

Movies

Gonad-icon.jpg
 ‎‎Testis
Page | Play
Male external 001 icon.jpg
 ‎‎Male External
Page | Play
Testis 001 icon.jpg
 ‎‎Testis Descent
Page | Play
Gonad blood 01 icon.jpg
 ‎‎Gonad Vascular
Page | Play


Links: Movies

Development Overview

Male urogenital development (stage 22)
Fetal gonad retinoid receptor expression[12]

Sex Determination

  • Humans (week 5-6)
  • Germ cells migrate into gonadal ridge
  • Gonads (male/female) identical at this stage, Indifferent

Gonad Development

  • dependent on sex chromosome
  • Y testes
  • No Y ovary

SRY

SRY protein (Testes determining factor, TDF) binds DNA Transcription factor, Bends DNA 70-80 degrees

Internal Genital Organs

  • All embryos form paired
  • Mesonephric duct, see kidney development
  • Paramesonephric duct, Humans 7th week Invagination of coelomic epithelium Cord grows and terminates on urogenital sinus
  • Male Gonad (testes) secretes Mullerian duct inhibitory factor (MDIF) which causes regression of paramesonephric duct
  • Male Gonad (testes) secretes Testosterone which retains mesonephric duct

External Genital Organs

  • All embryos initially same (indifferent)
  • Testosterone differentiates male

Week 8

Carnegie stage 22

Stage 22 image 302.jpg Stage 22 image 301.jpg

Developing testis is shown to the centre right. These images show the position, size and histological development of the testis in week 8 of human development (Carnegie stage 22, last embryonic week).

Human Stage 22: Testis - labeled overview | Testis - unlabeled overview | Testis - unlabeled detail | Testis - labeled detail | testis | Carnegie stage 22 | Movie - Urogenital stage 22

Sertoli Cells

Adult Seminiferous tubule showing spermatozoa developmental stages
Adult Seminiferous tubule showing spermatozoa developmental stages
Gonadal supporting cell development
Gonadal supporting cell development

The sertoli cell cells provide support for spermatozoa development within the seminiferous tubule. In the mouse, these cells are derived from the coelomic epithelium along with other testis somatic cells.[13] Their differentiation is regulated by the presence of a Y chromosome and in turn regulates Leydig cell differentiation. Sertoli cells direct testis morphogenesis, organizing testis cord formation, establishing testis vasculature and inducing differentiation of peritubular myoid cells and fetal Leydig cells. At puberty the immature Sertoli cells cease to proliferate and differentiate. Activin A acts upon Sertoli cells to promote their embryonic proliferation[14]

Sertoli cells express the androgen receptor and receptors for follicle stimulating hormone (FSH).


Sertoli cell functions include:

  • regulation of spermatogenesis through endocrine FSH and testosterone
  • regulation of the intratubular and intercellular environment adluminal to the tight junctional complexes
    • meiotic and post-meiotic germ cells are sequestered by Sertoli-Sertoli junctional complexes
  • generate adluminal compartment isolated from both serum and lymph
  • attachment of germ cells through unique intermediate filament (desmosome-like junctions) and microfilament (actin- ectoplasmic specializations, ESs) junctions[15]
    • to prevent premature sloughing of immature germ cells from the seminiferous epithelium
    • desmosome-like junctions are initially present (up to step 8 spermatids)
    • ectoplasmic specializations then replace this junction (in step 8 spermatids)

(see also review[16])

Ultrastructural description of human Sertoli cells[17]

  • 7 weeks - first morphologically recognised in testicular cords, organised as primordial germ cells surrounded by pre-Sertoli cells.
  • 7 to 8 weeks - basal lamina of the cords becomes distinguishable, pre-Sertoli cells the rough endoplasmic reticulum develops.
  • 14 to 20 weeks - pre-Sertoli cells maintain their general morphology whereas the most significant change is the maximum development of Leydig cells.

Molecular factors:

  • Follicle Stimulating Hormone (FSH) -> Krüppel-like factor 4 (KLF4)
  • Krüppel-like factor 4 (KLF4) - zinc finger transcription factor, terminal differentiation of epithelial cells.
  • Epidermal Growth Factor (EGF)
  • Transforming Growth Factor-beta (TGFbeta)


Links: sertoli cell

Leydig Cells

Seminiferous tubule cross-section and supporting cells

Interstitial or Leydig cell, named after German zoologist Franz von Leydig (1821 - 1908) who first histologically described them in 1850.[18] Their initial development appears to be influenced by Sertoli cell differentiation.

These cells produce the male testicular androgens and have a role during life prenatally (fetal) and postnatally during puberty onward.

Fetal Leydig cells develop from coelomic epithelium and undifferentiated perivascular cells in the gonad–mesonephros border region.

Adult Leydig cells appear after birth from stem/progenitor cells among peritubular and peri-vascular cells.

In the mouse both fetal and adult Leydig cells appear to arise from a common progenitor population.[19]


A recent study[20] has looked at the postnatal development of Leydig cells from stem cells:

  • early postnatal testis - interstitial compartment undifferentiated mesenchymal-like stem cells
  • adult testis - peritubular and perivascular locations quiescent stem cells (nestin, PDGFRα, COUP-TFII, CD51 and CD90)

Factors regulating division

  • proliferation - DHH (Desert hedgehog), FGF2, PDGFBB, activin and PDGFAA
  • suppression of proliferation - TGFβ, androgen and PKA signaling.

Fetal Leydig Cells

Fetal Leydig Cells (FLCs) have a hormonal role in male genitalia differentiation and are lost postnatally. The cells arise approximately at 6 weeks (human) and mouse E12.5 and there are differences in hormonal sensitivity between these two species. The cell initial differentiation requires both luteinizing hormone (LH) and adrenocorticotrophic hormone (ACTH) and therefore normal pituitary development.

Fetal Leydig Cells produce androstenedione but lack 17β-hydroxysteroid dehydrogenase (17β-HSD), to but produce testosterone. Fetal Sertoli cells do express 17β-HSD and can therefore convert androstenedione to testosterone.[21]

Links: pituitary

Adult Leydig Cells

Adult Leydig cells (ALCs) have a hormonal role in puberty, secondary sex characteristics and sexual maturation. Their initial differentiation from peritubular mesenchymal cells does not require gonadotropin, but development and function are dependent upon luteinizing hormone (LH).

The cells differentiate with three discrete stages (newly formed, immature, mature) leading to a decrease in proliferation and increasing testosterone biosynthetic capacity. Insulin-like growth factor I (IGF-I) stimulates proliferation of immature cells and promotes their maturation. Testosterone and estrogen inhibit the process of precursor cell differentiation and may be responsible for the cessation of proliferation in the adult Leydig cells.

Leydig Cell Electron Micrographs
Leydig cell PMID13693345 EM02.jpg Leydig cell PMID13693345 EM03.jpg
Low power EM High power EM

EM images above from historic study of the opossum testis.[22]

Testosterone

Leydig cells produce testosterone. Historically in 1935, Ernst Laqueur (Amsterdam, Netherlands) isolated testosterone, and Adolf Butenandt (Gdansk. Poland) and Leopold Ruzicka (Zürich, Switzerland) synthesised testosterone.[23]

Model male androsterone synthesis.jpg Proposed steroidogenic pathways leading to androsterone synthesis and masculinization in the second trimester human male fetus.[1]

Steroid hormone conversion is shown by wide green arrows, with the converting enzymes written within the arrow. Red arrows show potential transport between organs in the fetal circulation. The blue double-headed arrow indicates that exchange is also taking place between the placenta and the maternal circulation. Most circulating progesterone in the fetal circulation is likely to come from the placenta, and this will be reduced to 5αDHP by SRD5A1 in the placenta, fetal liver, and fetal testis, with the fetal liver likely to be the major site. Allopregnanolone (AlloP5) production by AKR1C2 is also most likely to occur in the placenta and fetal liver because the substrate is present in those tissues, and they express the highest total levels of enzyme transcript. Some conversion may also occur in the testis. Significant levels of androsterone are only detectable in the placenta and adrenal, and thus they are a likely source of the circulating steroid, although, given sex differences, other tissues are probably involved. The adrenal lacks other intermediates in the backdoor pathway, and thus AlloP5 must come from other tissues.

The placenta lacks CYP17A1, so androsterone production is likely to depend on adrenal DHEA as substrate. Testosterone from the fetal testes also acts as an essential substrate for DHT synthesis at the external genitalia.

AlloP5, allopregnanolone; An, androsterone; DHEA, dehydroepiandrosterone; DHT, 5α-dihydrotestosterone; P4, progesterone; P5, pregnenolone; T, testosterone; 5αDHP, 5α-dihydroprogesterone.


The adult testes produce about 6-10 mg /day in males (~0.5 mg / day in females) carried in circulation by a specific carrier globulin.

Peritubular Myoid Cells

The peritubular myoid cell surrounds the seminiferous tubule and have smooth muscle properties. Contraction of theses cells aids spermatozoa movement within the seminiferous tubule towards the epididymis for storage.


Tunica Albuginea

The capsule surrounding the testis is a multilayered fibrous structure. The main component of the capsule is the tunica albuginea composed dense collagen fibres, fibroblasts and smooth muscle cells.

Epididymis

testis histology
Human testis showing the epididymis (right)
Adult Epididymis Histology

Both the ductus epididymis and ductus deferens differentiate from the mesonephric duct (Wollfian duct) elongation (cell proliferation). In the case of the epididymis, elongation also is associated with extensive coiling, the adult human epididymis about 6 metres in length (mouse 1m, rat 3m). Embryonic growth is regulated by androgens, members of the PCP pathway, and inhibin beta A. While postnatally androgens and other growth factors may have roles in final maturation. (see review[24]) The ductus epididymis is lined by a very tall pseudostratified columnar epithelium, consisting of principal cells with long stereo cilia.

Following puberty, the epididymis is involved in maturation of the spermatozoa released from the seminiferous tubules and their storage.

  • middle segment - site of final functional maturation of the spermatozoa.
  • terminal segment - site of storage of the mature spermatozoa.
Nelsen1953 fig007.jpg Anatomically the adult epididymis is about 30 cm in length and consists of 3 regions:
  • Caput (head, globus major) upper enlarged extremity, consisting of a few tubes interconnecting at three levels.
  • Corpus (body, or central portion).
  • Cauda (tail, globus minor) lower pointed extremity, continuous with the ductus deferens (vas deferens).

The head is intimately connected with the upper end of the testis by means of the efferent ductules of the gland; the tail is connected with the lower end by cellular tissue, and a reflection of the tunica vaginalis (tunica vaginalis propria testis) the serous covering of the testis.

The lateral surface, head and tail of the epididymis are free and covered by the serous membrane; the body is also completely invested by it, excepting along its posterior border; while between the body and the testis is a pouch, named the sinus of the epididymis (digital fossa). The epididymis is connected to the back of the testis by a fold of the serous membrane.

Caput

In humans, the majority of the caput (head, globus major) is primarily efferent ducts and not epididymal duct, with multiple efferent ducts connecting to the main epididymal duct.[25]

Mouse postnatal epididymis development[26]

Adult Mouse Epididymis Histology[27]

Mouse- epididymis histology.jpg

Testis Descent

The research data on human testis descent timing has been highly variable. Testis descent is thought to have 2 phases:

  1. transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
  2. inguinoscrotal descent - dependent on androgens.

Other suggested factors with a role in descent include: gonadotropin-releasing hormone, fibroblast growth factors, Müllerian inhibiting substance, and inhibin B[28]

The regulation of testis descent is still being investigated and several different factors have been identified that may have roles in descent. The first stage of testicular descent occurs 10–15 weeks of gestation with the testes moving to the inguinal region. The second inguino-scrotal phase occurs between 25-35 weeks.[29]

Gubernaculum

The gubernaculum (gubernaculum Hunteri) is the caudal inguinoscrotal ligament that connects the testis to the lower abdomen. The cranial suspensory ligament (mesonephric ligament) is the cranial ligament that connects the tesitis to the posterior abdominal wall.

  • Insulin-like factor 3 (INSL3, relaxin-like factor) from fetal leydig cells acting through its receptor (Rxfp2) and BMP and WNT signaling pathways to promote testis descent.
  • Calcitonin gene-related peptide (CGRP) from genitofemoral nerve suggested to mediate the inguinoscrotal testicular descent.
  • Epidermal growth factor (EGF) may promote by activating the androgen responsive systems.


Testis-descent start.jpg Testis-descent end.jpg
Testis 001 icon.jpg
 ‎‎Testis Descent
Page | Play
Before Descent End of Descent Testis Descent Movie



Links: Search PubMed Gubernaculum| OMIM - INSL3

Puberty

Male testosterone and AMH level graph.jpg

Human Male Testosterone and Anti-Müllerian Hormone (AMH) relative levels[30]

  • AMH production by Sertoli cells .
  • Testosterone production by Leydig cells.

In humans at puberty, hormonal and morphological changes occur within the gonad and other systems (secondary sex characteristics). Within the testis the immature Sertoli cells cease to proliferate and differentiate. Spermatogonium proliferate and spermatogenesis begins, and it takes about 70 days for cells to mature from the diploid spermatogonium to a primary spermatocyte. This maturation occurs in waves along the seminiferous tubules.


Male puberty testicular volume graph

orchidometer
orchidometer

Male puberty testicular volume graph[31]

Testicular volume increase at puberty can be measured by: including orchidometry, rulers, calipers, and ultrasonography. There is also an earlier empirical formula developed by Lambert[32] used to estimate testicular volume.


Links: puberty

Orchidometer

(orchiometer) A simple clinical instrument used to measure postnatal testis volume using 12 beads ranging from 1 to 25 millilitres. Developed by Dr. Andrea Prader (1919 – 2001) an endocrinologist who also discovered the Prader-Willi syndrome and developed the Prader scale, a second clinical classification used to describe CAH virilization of female genitalia.


Blood-Testis Barrier

Rat blood–testis barrier
Rat blood–testis barrier[33]

Within the testis seminiferous tubules the Sertoli cells located near the basement membrane act as an initial cellular barrier with many functions, but often described as forming a "blood-testis barrier". (see review[34]

Functions:

  • prevent substances reaching the developing spermatozoa (through drug transporters)
  • establish a basal and adluminal (apical) compartment (specialized microenvironment)
  • provide an immunological privilege status of the testis (anti-sperm antibodies are not developed)
Tight Junctions Adherens Junctions
tight junctions adherens junctions
Germ cells first have to break through the tight junctions at the BTB with minimal disruptions. Progression of germ cells then relies on series of transient adherens junctions at the Sertoli–germ cell interface.
Assembly and disassembly of junctional complexes at the basal and apical ectoplasmic specialization occurs continuously.


Abnormalities

Male Infertility Genes

Selected genes in Male Infertility
Gene abbreviation Name Gene Location Online Mendelian
Inheritance in Man (OMIM)
HUGO Gene Nomenclature
Committee (HGNC)
GeneCards (GCID) Diagnosis
AURKC Aurora kinase C 19q13.43 603495 11391 GC19P057230 Macrozoospermia
CATSPER1 Cation channel sperm-associated 1 11q13.1 606389 17116 GC11M066034 Asthenozoospermia
CFTR Cystic fibrosis transmembrane conductance regulator 7q31.2 602421 1884 GC07P117465 Obstructive azoospermia
DNAH1 Dynein axonemal heavy chain 1 3p21.1 603332 2940 GC03P052350 Asthenozoospermia
DPY19L2 Dpy-19-like 2 gene 12q14.2 613893 19414 GC12M063558 Globozoospermia
GALNTL5 Polypeptide N-acetylgalactosaminyltransferase-like 5 7q36.1 615133 21725 GC07P151956 Asthenozoospermia
MAGEB4 MAGE family member B4 Xp21.2 300153 6811 GC0XP030260 Azoospermia
NANOS1 Nanos C2HC-type zinc finger 1 10q26.11 608226 23044 GC10P119029 Azoospermia
NR0B1 Nuclear receptor subfamily 0 group B member 1 Xp21.2 300473 7960 GC0XM030322 Azoospermia
NR5A1 Nuclear receptor subfamily 5 group A member 1 9q33.3 184757 7983 GC09M124481 Azoospermia
SOHLH1 Spermatogenesis and oogenesis-specific basic helix–loop–helix 1 9q34.3 610224 27845 C09M135693 Azoospermia
vSPATA16 Spermatogenesis-associated 16 3q26.31 609856 29935 GC03M172889 Globozoospermia
SYCE1 Synaptonemal complex central element protein 1 10q26.3 611486 28852 GC10M133553 Azoospermia
TAF4B TATA-box binding protein-associated factor 4b 18q11.2 601689 11538 GC18P026225 Azoospermia
TEX11 Testis expressed 11 Xq13.1 300311 11733 GC0XM070528 Azoospermia
TEX15 Testis expressed 15, meiosis and synapsis associated 8p12 605795 11738 GC08M030808 Azoospermia
WT1 Wilms tumour 1 8p12 607102 12796 GC11M032365 Azoospermia
ZMYND15 Zinc-finger MYND-type containing 15 17p13.2 614312 20997 GC17P004740 Azoospermia
  Table data source[35] (table 1)    Links: fertilization | spermatozoa | testis | Male Infertility Genes | Female Infertility Genes | oocyte | ovary | Genetic Abnormalities | ART

  Asthenozoospermia - (asthenospermia) term for reduced spermatozoa motility. Azoospermia - term for no spermatozoa located in the ejaculate. Globozoospermia - term for spermatozoa with a round head and no acrosome.

International Classification of Diseases

 ICD-11 5A81 Testicular dysfunction or testosterone-related disorders
  • LB51 Anorchia or microorchidia - A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by individuals who are born with absence of the testes, or with testes that are deficient in size and function. Confirmation is by physical examination, identification of low testosterone levels but elevated follicle stimulating hormone and luteinizing hormone levels in a blood sample, or imaging.
  • LB58 Polyorchidism - A condition of the testes, caused by determinants arising during the antenatal period. This condition is characterized by the presence of more than two testicles. Confirmation is by imaging.
  • 5A81.1 Testicular hypofunction - In pre-puberty, a disorder characterized by atrophied testes and sterility, abnormal height and absence of secondary sex characteristics. In post-puberty, a disorder characterized by depressed sexual function, loss of sex drive and sterility, muscle weakness and osteoporosis (due to loss of the androgen anabolic effect).
  • GB04.0 Azoospermia - Any condition of the genital system affecting males, caused by obstruction of the reproductive tract, abnormal hormone levels, testicular failure, or inadequate production of spermatozoa. These conditions are characterized by the absence of a measurable level of sperm cells in semen, and very low levels of fertility. Confirmation is by the absence of spermatozoa in the sediment of a centrifuged sample of ejaculate.
  • GB03 Atrophy of testis - A condition of the testis, caused by apoptosis of the cells due to diminished cellular proliferation, decreased cellular volume, decreased function, ischemia, malnutrition, disease, infection, mutation, or hormonal changes. This condition is characterized by a partial or complete decrease in size and function of the testis tissue.
  • GB00 Hydrocele or spermatocele - A condition characterized by an accumulation of serous fluid in the tunica vaginalis testis or along the spermatic cord, and cystic swelling containing fluid and dead spermatozoa of the testicular epididymis, rete testis or efferent ductuli.
  • LB52 Cryptorchidism - A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by the absence of one or both testes from the scrotum. This disorder may also present with reduced fertility, psychological implications, or increased risk of testicular germ cell tumours. Confirmation is by imaging, karyotyping, or identification of male sex hormones in a blood sample.
genital abnormalities |  ICD-11

Cryptorchidism

 ICD-11 LB52 Cryptorchidism - A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by the absence of one or both testes from the scrotum. This disorder may also present with reduced fertility, psychological implications, or increased risk of testicular germ cell tumours. Confirmation is by imaging, karyotyping, or identification of male sex hormones in a blood sample.
Newborn - cryptorchidism normal birthweight[36]

The external location of the testes in the scrotum acts as a local thermo-regulator and provides a temperature environment below that of the general body temperature.[37] This thermal function is essential for normal spermatogenesis and cryptorchidism therefore affects fertility.

  • 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:

  1. transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
  2. inguinoscrotal descent - dependent on androgens.

Management of cryptorchidism in children: guidelines.[38] "Cryptorchidism is best diagnosed clinically, and treated by surgical orchiopexy at age 6-12 months, without a routine biopsy. If no testis is palpable, or if other signs of hypovirilisation such as hypospadias are present, the chromosomal sex and hormonal status must be assessed. Laparoscopy is the best way of diagnosing and managing intra-abdominal testes."

Links: cryptorchidism

Anorchia

 ICD-11 LB51 Anorchia or microorchidia - A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by individuals who are born with absence of the testes, or with testes that are deficient in size and function. Confirmation is by physical examination, identification of low testosterone levels but elevated follicle stimulating hormone and luteinizing hormone levels in a blood sample, or imaging.

Clinical term for (embryonic testicular regression, vanishing testis syndrome) the absence of testes in a 46,XY individual with a male phenotype. Rare abnormality with an incidence of about 1 in 20,000 male births, and occurs more frequently with cryptorchidism (1 in 177 cases).

A recent study has identified undetectable plasma concentrations of anti-Müllerian hormone (AMH) and inhibin B and an elevated plasma FSH, together with 46,XY complement are sufficient for diagnosis of anorchia. Genetic analysis showed that NR5A1 and other genes (INSL3, SRY, LGR8 , MAMLD1) implicated in gonadal development and testicle descent were also not mutated.[39]


Myotonic dystrophy type 1

Postnatal muscular dystrophy resulting in myotonia, muscle weakness, abnormalities of heart, lungs, eye, brain and endocrine system. There is an associated progressive testicular atrophy (about 80% affected males) leading to Leydig cell hyperproliferation and elevated basal levels of follicle stimulating hormone (FSH).[40]

Histology

Testis Histology Links: Testis Development | Spermatozoa Development | Histology

Human (young): overview labeled | overview unlabeled | convoluted seminiferous tubules x10 | x40 | x40 | tunica albuginea x20
Human (adult): overview x2 | convoluted seminiferous tubules labeled | x10 | x20 | x40 | x40 | epididymis ductulus efferens | ductus epididymidis | epithelium | overview x4 | x10 | x20 | x40 | ductus deferens labeled overview | epithelium | overview x2 | x10 | x40
Human spermatozoa: x20 | x40 | x100
Human Stage 22: Testis - labeled overview | Testis - unlabeled overview | Testis - unlabeled detail | Testis - labeled detail | testis | Carnegie stage 22 | Movie - Urogenital stage 22
Rabbit: convoluted seminiferous tubules x20 | x100
Mouse: postnatal epididymis | 14 days postnatal | 33 days postnatal | 45 days postnatal | 2 months postnatal
Spermatozoa Development (expand to see terms)  

Spermatozoa Development

Note there are additional glossaries associated with genital, spermatozoa, oocyte and renal.

Spermatozoon
  • acroplaxome - structure forms the acrosome plate with intermediate filament bundles of the marginal ring at the leading edge of the acrosome. The sub-acrosomal layer located in the developing spermatozoa head perinuclear region, located between the inner acrosomal membrane and the nuclear envelope. The other part of the perinuclear region is the post-acrosomal sheath (PAS) at the post-acrosomal region.
  • acrosome - Cap-shaped cellular structure formed from the golgi apparatus and contains enzymes to dissolve the oocyte (egg) zona pellucida for fertilisation.
  • acrosome compaction - Acrosome reshaping process in final stages of spermatogenesis (spermatid to spermatozoa).
  • acrosome reaction - Chemical change within the spermatozoa following binding to the zona pellucida, only acrosome reacted spermatozoa have an ability to fuse with oocytes.
  • annulus - Cytoskeletal (septin) structure located between the midpiece and principal piece regions of the tail, thought to form a diffusion barrier between these two domains. PMID 20042538
  • asthenozoospermia - (asthenospermia) Term for reduced sperm motility and can be the cause of male infertility.
  • axoneme - (axonema) The basic structure in cilia and eukaryotic flagella and in the spermatozoa tail, consisting of parallel microtubules in a characteristic "9 + 2" pattern. This pattern describes 9 outer microtubule doublets (pairs) surrounding 2 central singlet microtubules, in humans 50 μm long. The motor protein dynenin move the outer microtubules with respect to the central pair, bending the cilia and generating motility. Note that prokaryotic bacteria have a similar process (flagellum) that uses an entirely different mechanism for motility.
  • capacitation - term describing the process by which spermaozoa become capable of fertilizing an oocyte, requires membrane changes, removal of surface glycoproteins and increased motility.
  • caput - proximal head of the epididymis, epithelium with stereocilia, involved in absorbing fluid to concentrate spermatozoa. Underlying smooth muscle aids movement. Epididymis three main parts : caput (head), corpus (body), cauda (tail).
  • CatSper - cationic (Ca2+) channel of spermatozoa, progesterone activated involved in hyperactivation, acrosome reaction, and possibly chemotaxis.
  • cauda - distal tail of the epididymis, region with a thin epithelium and the greatest quantity of smooth muscle. Epididymis three main parts : caput (head), corpus (body), cauda (tail).
  • centriole - a microtubule organising centre. First required for axoneme formation (distal centriole) that is lost and a second for pronuclei formation (proximal) following fertilisation. Rodents loose both and only have maternal centrioles.
  • connecting piece - linkage between the spermatozoa head and the midpiece of the tail. PMID 22767409
  • corpus - elongated body of the epididymis, This has an intermediate thickness of epithelium and thicker smooth muscle layer than caput. Epididymis three main parts : caput (head), corpus (body), cauda (tail).
  • cytoplasmic bridges - Transient cytoplasm connections between spermatids arising from one spermatogonium due to incomplete cytokinesis.
  • diploid - (Greek, di = double + ploion = vessel) Having two sets of chromosomes, the normal state for all cells other than the gametes.
  • end piece - Last portion of the spermatozoa tail region.
  • epididymis - testis tubular structure connecting the efferent ducts to the ductus deferent and functions for the storage and maturation of spermatozoa. Epididymis three main parts : caput (head), corpus (body), cauda (tail). PMID27307387
  • fibrous sheath - cytoskeletal structure surrounding the axoneme and outer dense fibers, defining the extent of the principal piece region.
  • haploid - (Greek, haploos = single) Having a single set of chromosomes as in mature germ/sex cells (oocyte, spermatozoa) following reductive cell division by meiosis. Normally cells are diploid, containing 2 sets of chromosomes.
  • interstitial cell - (Leydig cell) Male gonad (testis) cell which secrete the androgen testosterone, beginning in the fetus.
  • interstitium - testis developmental region (space between testis cords) that generates Leydig cells and other less well characterized cell types.
  • Johnsen score - a clinical score (1-10) for assessing spermatogenesis in a human testicular biopsy. Named after the author of the original article. PMID 5527187
  • Leydig cell - (interstitial cell) Male gonad (testis) cell that secrete the androgen testosterone, beginning in the fetus. Fetal Leydig cells develop from coelomic epithelium and undifferentiated perivascular cells in the gonad–mesonephros border region. Adult Leydig cells appear after birth from stem/progenitor cells among peritubular and peri-vascular cells. Leydig cells were first histologically identified in 1850 by Franz von Leydig (1821 - 1908) a German scientist.
  • meiosis - The cell division that occurs only in production of germ cells where there is a reduction in the number of chromosomes (diploid to haploid) which is the basis of sexual reproduction. All other non-germ cells in the body divide by mitosis.
  • midpiece - (middle piece) spermatozoa tail initial segment of axoneme surrounded outer dense fibres then by mitochondria. Next in the tail is the principal piece then finally the end piece.
  • mitosis - The normal division of all cells, except germ cells, where chromosome number is maintained (diploid). In germ cell division (oocyte, spermatozoa) meiosis is a modified form of this division resulting in reduction in genetic content (haploid). Mitosis, division of the nucleus, is followed by cytokinesis the division of the cell cytoplasm and the cytoplasmic contents. cytokinesis overlaps with telophase.
  • outer dense fibres - (ODF, outer dense fibers) cytoskeletal structures that surround the axoneme in the middle piece and principal piece of the spermatozoa tail.
  • primary spermatocyte - arranged in the seminiferous tubule wall deep (luminal) to the spermatogonia. These large cells enter the prophase of the first meiotic division. (More? meiosis)
  • principal piece - Spermatozoa tail segment containing the plasma membrane calcium channels (CatSper1 and CatSper2) required for hyperactivation of motility. Region is partially separated from the midpiece by a barrier called the annulus.
  • sertoli cells - (sustentacular cell) These cells are the spermatozoa supporting cells, nutritional and mechanical, as well as forming a blood-testis barrier. The cell cytoplasm spans all layers of the seminiferous tubule. The cells are named after Enrico Sertoli (1842 - 1910), and italian physiologist and histologist.
  • sperm annulus - (Jensen's ring; Latin, annulus = ring) A region of the mammalian sperm flagellum connecting the midpiece and the principal piece. The annulus is a septin-based structure formed from SEPT1, 4, 6, 7 and 12. Septins are polymerizing GTPases that can act as a scaffold forming hetero-oligomeric filaments required for cytokinesis and other cell cycle roles.
  • spermatogenesis - (Greek, genesis = origin, creation, generation) The term used to describe the process of diploid spermatagonia division and differentiation to form haploid spermatazoa within the testis (male gonad). The process includes the following cellular changes: meiosis, reoorganization of DNA, reduction in DNA content, reorganization of cellular organelles, morphological changes (cell shape). The final process of change in cell shape is also called spermiogenesis.
  • spermatogenesis - (Greek, genesis = origin, creation, generation) The maturation process of the already haploid spermatazoa into the mature sperm shape and organization. This process involves reorganization of cellular organelles (endoplasmic reticulum, golgi apparatus, mitochondria), cytoskeletal changes (microtubule organization) and morphological changes (cell shape, acrosome and tail formation).
  • spermatogonia - The cells located in the seminiferous tubule adjacent to the basal membrane that either divide and separate to renew the stem cell population, or they divide and stay together as a pair (Apr spermatogonia) connected by an intercellular cytoplasmic bridge to differentiate and eventually form spermatazoa.
  • spermatozoa head - Following spermiogenesis, the first region of the spermatozoa containing the haploid nucleus and acrosome. In humans, it is a flattened structure (5 µm long by 3 µm wide) with the posterior part of nuclear membrane forming the basal plate region. The human spermatozoa is about 60 µm long, actively motile and divided into 3 main regions (head, neck and spermatozoa tail).
  • spermatozoa neck - Following spermiogenesis, the second region of the spermatozoa attached to basal plate, transverse oriented centriole, contains nine segmented columns of fibrous material, continue as outer dense fibres in tail. In humans, it forms a short structure (1 µm). The human spermatozoa is about 60 µm long, actively motile and divided into 3 main regions (head, neck and tail).
  • spermatozoa tail - Following spermiogenesis, the third region of the spermatozoa that has a head, neck and tail). The tail is also divided into 3 structural regions a middle piece, a principal piece and an end piece. In humans: the middle piece (5 µm long) is formed by axonema and dense fibres surrounded by mitochondria; the principal piece (45 µm long) fibrous sheath interconnected by regularly spaced circumferential hoops; the final end piece (5 µm long) has an axonema surrounded by small amount of cytoplasm and plasma membrane.
  • spermatogonial stem cells - (SSCs) The spermatagonia cells located beside the seminiferous tubule basal membrane that either divide and separate to renew the stem cell population, or they divide and stay together as a pair (|Apr spermatogonia) connected by an intercellular cytoplasmic bridge to differentiate and eventually form spermatazoa.
  • spermatozoon - singular form of of spermatozoa.
  • sperm protein 56 - A component of the spermatozoa acrosomal matrix released to the sperm surface during capacitation.
  • teratospermia - Clinical term for a spermatozoa with abnormal morphology (small, large, defects in the head, tail, and/or mid-piece) present in the semen or ejaculate.
  • testis cords - developmental structure that give rise to the adult seminiferous tubules, the other developmental region is the interstitium.
  • vasectomy - Clinical term for ligation of the scrotal portion of the ductus deferens.

See also: Spermatozoa Terms collapse table

Other Terms Lists  
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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 
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
Links: Spermatozoa Histology | Histology Stain H&E | Histology Stains

Molecular

Sry

  • Y chromosome gene for a transcription factor
  • member of the high mobility group (HMG)-box family of DNA binding proteins
  • human - 204 amino acid protein[41]
Links: OMIM - Sry

Sox9

Recent studies have identified upstream SOX9 enhancers that when duplicated or deleted result in 46,XX or 46,XY sex reversal, respectively.[42][43]


  • autosomal transcription factor
  • Development of XY females - presence of only a single functional copy of the transcription factor encoding genes SOX9, SF1, or WT1 (Note- not all XY humans are sex-reversed if only a single copy of a normal SF1 or WT1 allele is present)
  • A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination[44]

Other roles

  • Cartilage - essential for chondrocyte differentiation
  • Hearing - otic placode formation, maintenance of progenitors in the otic epithelium


Links: OMIM Sox9 | cartilage | inner ear

Fog2

  • transcription factor, named Friend of Gata2
  • human - (8q23) 1,151 amino acid nuclear protein that contains 8 zinc finger motifs[45]
  • dosage critical for fetal testis development in mice[46]
Links: OMIM - Fog2

Gadd45g

Gadd45g and Sex Determination Model[2]

Growth Arrest- And Dna Damage-Inducible Gene (GADD45, GAMMA; GADD45G)

A Recent mouse study[2] has shown that Gadd45g protein has a role in primary sex differentiation. Knockout mice (Gadd45g(-/-) XY gonads) resulted in a a sex reversal.


Links: OMIM - Gadd45g

Gata4

  • transcription factor
  • dosage critical for fetal testis development in mice[46]

Eif2s3y

References

  1. 1.0 1.1 O'Shaughnessy PJ, Antignac JP, Le Bizec B, Morvan ML, Svechnikov K, Söder O, Savchuk I, Monteiro A, Soffientini U, Johnston ZC, Bellingham M, Hough D, Walker N, Filis P & Fowler PA. (2019). Alternative (backdoor) androgen production and masculinization in the human fetus. PLoS Biol. , 17, e3000002. PMID: 30763313 DOI.
  2. 2.0 2.1 2.2 2.3 Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M & Salvador JM. (2013). Gadd45g is essential for primary sex determination, male fertility and testis development. PLoS ONE , 8, e58751. PMID: 23516551 DOI.
  3. Sakashita A, Wakai T, Kawabata Y, Nishimura C, Sotomaru Y, Alavattam KG, Namekawa SH & Kono T. (2019). XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage†. Biol. Reprod. , 100, 697-710. PMID: 30289439 DOI.
  4. Chimote BN & Chimote NM. (2018). Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEA-S) in Mammalian Reproduction: Known Roles and Novel Paradigms. Vitam. Horm. , 108, 223-250. PMID: 30029728 DOI.
  5. Hoshi M, Reginensi A, Joens MS, Fitzpatrick JAJ, McNeill H & Jain S. (2018). Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion. J. Am. Soc. Nephrol. , 29, 775-783. PMID: 29326158 DOI.
  6. Wen Q, Wang Y, Tang J, Cheng CY & Liu YX. (2016). Sertoli Cell Wt1 Regulates Peritubular Myoid Cell and Fetal Leydig Cell Differentiation during Fetal Testis Development. PLoS ONE , 11, e0167920. PMID: 28036337 DOI.
  7. Caruso M, Ferranti F, Corano Scheri K, Dobrowolny G, Ciccarone F, Grammatico P, Catizone A & Ricci G. (2015). R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis. PLoS ONE , 10, e0124213. PMID: 25910078 DOI.
  8. Bormann CL, Smith GD, Padmanabhan V & Lee TM. (2011). Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testicular development. Reproduction , 142, 167-73. PMID: 21493716 DOI.
  9. Pask AJ, Calatayud NE, Shaw G, Wood WM & Renfree MB. (2010). Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal. BMC Biol. , 8, 113. PMID: 20807406 DOI.
  10. Kleisner K, Ivell R & Flegr J. (2010). The evolutionary history of testicular externalization and the origin of the scrotum. J. Biosci. , 35, 27-37. PMID: 20413907
  11. Hiramatsu R, Harikae K, Tsunekawa N, Kurohmaru M, Matsuo I & Kanai Y. (2010). FGF signaling directs a center-to-pole expansion of tubulogenesis in mouse testis differentiation. Development , 137, 303-12. PMID: 20040496 DOI.
  12. Childs AJ, Cowan G, Kinnell HL, Anderson RA & Saunders PT. (2011). Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. PLoS ONE , 6, e20249. PMID: 21674038 DOI.
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Reviews

de Mello Santos T & Hinton BT. (2019). We, the developing rete testis, efferent ducts, and Wolffian duct, all hereby agree that we need to connect. Andrology , , . PMID: 31033257 DOI.

Harpelunde Poulsen K & Jorgensen A. (2019). Role of Nodal signalling in testis development and initiation of testicular cancer. Reproduction , , . PMID: 30999282 DOI.

Stévant I & Nef S. (2019). Genetic Control of Gonadal Sex Determination and Development. Trends Genet. , 35, 346-358. PMID: 30902461 DOI.

Rotgers E, Jørgensen A & Yao HH. (2018). At the crossroads of fate - somatic cell lineage specification in the fetal gonad. Endocr. Rev. , , . PMID: 29771299 DOI.

Stévant I & Nef S. (2018). Single cell transcriptome sequencing: A new approach for the study of mammalian sex determination. Mol. Cell. Endocrinol. , 468, 11-18. PMID: 29371022 DOI.

Barton LJ, LeBlanc MG & Lehmann R. (2016). Finding their way: themes in germ cell migration. Curr. Opin. Cell Biol. , 42, 128-137. PMID: 27484857 DOI.

De Felici M. (2016). The Formation and Migration of Primordial Germ Cells in Mouse and Man. Results Probl Cell Differ , 58, 23-46. PMID: 27300174 DOI.

Virtanen HE & Toppari J. (2014). Embryology and physiology of testicular development and descent. Pediatr Endocrinol Rev , 11 Suppl 2, 206-13. PMID: 24683945

Svingen T & Koopman P. (2013). Building the mammalian testis: origins, differentiation, and assembly of the component cell populations. Genes Dev. , 27, 2409-26. PMID: 24240231 DOI.

Hinton BT, Galdamez MM, Sutherland A, Bomgardner D, Xu B, Abdel-Fattah R & Yang L. (2011). How do you get six meters of epididymis inside a human scrotum?. J. Androl. , 32, 558-64. PMID: 21441421 DOI.

Griswold SL & Behringer RR. (2009). Fetal Leydig cell origin and development. Sex Dev , 3, 1-15. PMID: 19339813 DOI.

Articles

Nef S & Wilhelm D. (2018). The impact of new technologies in our understanding of testis formation and function. Mol. Cell. Endocrinol. , 468, 1-2. PMID: 29807571 DOI.

Kaftanovskaya EM, Feng S, Huang Z, Tan Y, Barbara AM, Kaur S, Truong A, Gorlov IP & Agoulnik AI. (2011). Suppression of insulin-like3 receptor reveals the role of β-catenin and Notch signaling in gubernaculum development. Mol. Endocrinol. , 25, 170-83. PMID: 21147849 DOI.

Stukenborg JB, Colón E & Söder O. (2010). Ontogenesis of testis development and function in humans. Sex Dev , 4, 199-212. PMID: 20664245 DOI.

Hutson JM, Balic A, Nation T & Southwell B. (2010). Cryptorchidism. Semin. Pediatr. Surg. , 19, 215-24. PMID: 20610195 DOI.

Adham IM & Agoulnik AI. (2004). Insulin-like 3 signalling in testicular descent. Int. J. Androl. , 27, 257-65. PMID: 15379965 DOI.

Heyns CF. (1987). The gubernaculum during testicular descent in the human fetus. J. Anat. , 153, 93-112. PMID: 2892824

Books

De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A & Hutson JM. (2000). Cryptorchidism and Hypospadias. , , . PMID: 25905331

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Cite this page: Hill, M.A. (2019, September 17) Embryology Testis Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Testis_Development

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