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Home , Rete testis, Seminiferous tubule, Sertoli cell, Spermatocyte, Tubule, Vaginal process

Structure of the Testis

Vas Deferens Caput

Endocrinology of the Testis Vas Efferentia Seminiferous 6-12

John Parrish Corpus Epididymis References: Williams Textbook of (within the mediastinum) Cauda Epididymis

Seminiferous Mediastinum Tubule Rete Testis Spermatogonia

Primary Sertoli Cells Myoid Cells »Support Secondary Spermatocyte Leydig Cells » Round synthesis Spermatozoa

Basement Membrane The Testis

Sertoli Migration

Migration begins by the 4 week of gestation in cow and human.

1 Migration from through .

XY Male Y Circulating Androgen SRY, SOX9

Testes develop • Sex Binding Globulin - 44% • Albumin - 54% (1000 fold less affinity than

Leydig Cells Sertoli Cells SHBG) Differentiate Differentiate • Free - 2% SF-1 SF-1 5a-red Bioavailable Testosterone = free + albumin bound Testosterone DHT AMH AR AR SHBG is made in Liver Development of AMHR Development ABP is made in Sertoli Cells of Wollfian and Ducts Degeneration of accessory Both also bind Mullerian Duct sex glands

Undifferentiated AMH AMH

2 Differentiated Reproductive Tracts Testicular Development Female Male (Wolffian Duct)

Rete Tubules

Mullerian Duct Tunica Undifferentiated Albuginea Sex Chords

Mesonephric Tubules Primary Sex Chords in Fetal Testis Rete Tubules Pre-Sertoli - AMH

Wolffian Duct

Leydig Cells - Testosterone

Mullerian Duct Primary, Epithelial or Medullary Sex Chords Tunica • Primordial germ cells Albuginea () • Pre-Sertoli Cells

FSH on Sertoli Cells • estradiol GnRH • inhibin Negative Feedback • ABP • tight junctions • growth factors • Hypothalamus Ant. Pituitary Negative Feedback of » Testosterone conversion to Estradiol Estradiol and Inhibin » Androgen receptor is less important Negative To • LH FSH Epid. Feedback of ABP » Adrogen receptor involved because DHT has Androgens + negative feedback as well testosterone E2 T Leydig » Aromatization of testosterone to estradiol also Cells Inhibin Sertoli occurs Cells T » Inhibin TJ Germ Cells ABP Seminiferous Tubule

3 and Hypothalamus Interactions GnRH

Ant. Pituitary

Fetal Leydig E2 Cells Pre-Sertoli T Cells Gonocytes AMH Primary Sex Chord

Testosterone Levels: Fetus - Adult Testicular Descent

Fetal Neonatal Pubertal Adult Fusion of the tunica 5.0 albuginea and to form the visceral 2.5 Adult Leydig Cells Fetal Leydig Cells Plasma Testosterone ng/ml

Birth

Rapid growth Cranial of Spermatic Artery Front View Spermatic Artery Suspensory Ligament Cranial Peritoneum (disappears) Suspensory Ligament Visceral Growth Visceral Growth Fusion of Peritoneum Inguinal Ring and Testis Testis Gubernaculum Peritoneum Gubernaculum Gubernaculum (rapid growth) Parietal Tunica Vaginalis Peritoneum Testis is pulled down Inguinal Ring Visceral Tunica to the inguinal Vaginalis ring.

4 Gubernaculum Spermatic Artery Spermatic Artery regresses Continued regression of Peritoneum Peritoneum Gubernaculum Visceral Growth Visceral Growth Testis pulled deeper Inguinal Canal into Scrotum Peritoneum Peritoneum Testis Vaginal Process Vaginal Vaginal Process attaches to Scrotum Process Gubernaculum (Regressing) Testis Parietal Tunica Space between Parietal Tunica Vaginalis Visceral and Parietal T.V. Vaginalis is continuous with Visceral Tunica Testis pulled into Visceral Tunica Peritoneum Vaginalis scrotum Vaginalis Gubernaculum (Fully Regressed)

Testicular Descent Timing of Testicular Descent in Mammals

Gonad Adominal Pause Transinguinal Inguinoscrotal • Cryptorchid - failure of descent to testis Translocation • Controlling mechanisms Testis in » Androgen dependent Cattle Scrotum » DHT supported Deer » inhibits Human • Gene Expression Horse » INSL3 - like growth factor 3 Pig – From leydig cells Dog » Great/LGR8 - receptor for INSL3 – In gubernaculum Mouse 0 20 40 60 80 Birth 120 140 Interval After Conception (% of Gestation)

Normal Dog Seminiferous Tubule Cryptorchid Dog Seminiferous Tubule

Increased Chance of Testicular Sertoli Cells

5 Primary Sex Chord to Seminiferous Tubule Primary Sex Chord to Seminiferous Tubule

Primodial Sertolic Primodial Sertolic Germ Cell Cell Germ Cell Cell (PGC) Precursor (PGC) Precursor

Proliferate to form Spermatogonial Stem Cells

Stem Cell Niche •Along basement membrane

FSH on Sertoli Cells Primary Sex Chord to Seminiferous Tubule Hypothalamus • estradiol GnRH • inhibin • ABP Primodial Sertolic • tight junctions • growth factors Germ Cell Cell Ant. (PGC) Precursor Pituitary Negative Feedback of Estradiol and Inhibin

Negative To PGC and Proliferate to LH FSH Epid. Spermatogonia form Feedback of ABP Spermatogonial Androgens + a a E2 T • Express 3-, 5-, Stem Cells Leydig aV-, b1-integrins Cells Inhibin Sertoli • Initially express c- T Cells kit receptor, then TJ Germ stop Stem Cell Niche Cells ABP Seminiferous •Along basement membrane Tubule

Sertoli Cell Regulation Sertoli Cell Regulation (cont.)

• Switch from FSH to Testosterone • FSH causes Sertoli cells to secret factors » FSH causes increase in cAMP that increase Leydig cell response to LH » at , phosphodiesterase increases » at puberty or start of breeding season – FSH less effective – FSH increases first » Testosterone takes over regulation – Sertoli cells trigger the development of SER in Leydig • Germ cells effect ability of Sertoli cell to cells respond to testosterone

6 Hormonal Regulation of Spermatogenesis Hormonal Regulation of Spermatogenesis (Cont.) • Level of Testosterone • Why is testosterone so high in STF? » intratesticular testosterone is higher than in circulation » Does testosterone work by androgen receptor? IF 600 nM (Leydig cells here) – Yes, DHT is more effective than testosterone TV 250 nM » What is level of free testosterone in STF? SV 150 nM – Have not been able to measure PV 20 nM – ABP is produced by sertoli cells under influence of FSH It is usually 30 to 170 times that seen in PV and is present at 30 - 40 nM » Seminiferous Tubule Fluid (STF) testosterone • Certainly reduces free testosterone but there is still STF 170 nM excess testosterone

» Androgen receptor Kd for testosterone » Artificial testosterone via implants found need 75 3 nM nM to maintain spermatogenesis

Hormonal Regulation of Spermatogenesis (Cont.) Mitotic Divisions of Spermatogenesis

• Level of testosterone in Sertoli cell As Apr Aal - stem cells, resting pool, slow dividing » Testosterone is converted to estrogen in sertoli cell A type spermatogonia (1 - 4 types ) » Has not been addressed • No good answer Intermediate spermatogonia

B type spermatogonia

Primary spermatocyte

Mitotic Divisions of Spermatogenesis Meiotic Divisions of Spermatogenesis

As Apr Aal - stem cells, resting pool, slow dividing Primary spermatocyte - long interval

A type spermatogonia (1 - 4 types ) • preleptotene - DNA synthesis • leptotene - condensation of the Random Divisions Intermediate spermatogonia • zygotene - thickening of and pairing • pachytene - RNA synthesis, thickening of chromosomes, crossing over B type spermatogonia • diplotene - chromosomes separate but remain attached at chiasma Stage Specific • diakinesis - cells separate and divide Primary spermatocyte Divisions

7 Meiotic Divisions (cont.) Chromatin Sturcture

Primary spermatocyte

Secondary spermatocyte - short lived and undergoes reduction division

Round

Spermiation

Cytoplasmic Elimination Phase and Spermiation Seminiferous Tubule

• residual body loss • phagocytosis by sertoli cell • elong. sperm. influences sertoli cell –sem. tubual fluid –ABP –inhibin –interleukin 1

Amann 1983 Lumen

Adluminal

Spermatids 1° Spermatocyte

Basal Sertoli Cell

Interstitial Leydig Cell Vessel

8 Cytoplasmic Bridges Present Among Daughter Cells Over Population of Spermatogonia All develop Tight Junction surrounded by 1 Formation - FSH Sertoli cell ! Sertoli Sertoli Maintenance - T SG SG SG SG SG SG SG SG SG Basement Membrane Normal Inhibited

PS Sertoli SG Sertoli PS Sertoli SG Sertoli AP AP SG SG SG SG SG AP SG AP SG SG SG SG SG SG Degenerating Spermatogonia (Apoptosis, as high as 75%) Basement Membrane Basement Membrane

Spermatogenesis Every 13.5 Days sperm are released from this point Ap Spermatogonial Ad Renewal in the Spermatid Stem Cell FSH Primate Round Pool Spermatid Secondary Spermatocyte B Sertoli Cells Primary Spermatocyte

P Spermatogonia

Every 13.5 Days a new group of cells initiate the cycle Myoid Cells

Stages Cycle

• Specific cellular associations within a small • progression through sequence of all stages segment of a seminiferous tubule

• stages are not the same length in time

9 Normal Apoptosis Effect of Hormone Withdrawal

• Experimental Approaches » Hypox. – can’t restore with testosterone alone » GnRH agonist – Decreased FSH and LH release – Requires both FSH and Testosterone to get normal spematogenesis » Ethane dimethane sulfonate (destroys leydig cells) – get destruction of spermatogenesis – testosterone can overcome effects of EDS except does not prevent destruction of Leydig cells

Essential

Prevents Apoptosis

Testosterone Effects

10 FSH Effects

Prevents Apoptosis N-cadherin loss FSH + T N-cadherin N-cadherin

SCF Activin SCF Activin SCF SCF B to P promoted

FSH Receptors Highest Testosterone Effects FSH Receptors Highest Testosterone Effects

Normal Dog Seminiferous Tubule

N-cadherin loss

N-cadherin

Activin SCF SCF

FSH Receptors Highest Testosterone Effects

Human Male Reproductive Tract Human Testis

Hormonal Dependence •Testosterone »Wolfian Duct §Vas efferentia §Epididymis § § •DHT »Rest of Male Structures § §Cowper’s §Penis

11 Human Male Reproductive Tract and Bladder Hyperplasia of Human Prostate Bladder • DHT driven via Androgen Receptor • 5-α-reductase inhibitors common treatment » Type 2 enzyme in prostate, hair follicle Seminal Vesicles – No effect on libido – Hair follicles and other DHT dependent tissue affected • Estradiol increases androgen receptor in prostate and estradiol increase with age Prostate Vas Deferens

Primary Sex Chord to Seminiferous Tubule

Primodial Sertolic Germ Cell Cell (PGC) Precursor The End PGC and Stem Cell Proliferate to Spermatogonia form Spermatogonial a a • Express 3-, 5-, Stem Cells aV-, b1-integrins • Initially express c- kit receptor, then stop Stem Cell Niche •Along basement membrane

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