Organogenesis 4 - The Urogenital System PDF

Even thought the urinary system and the reproductive system have a functional separation they are anatomically intertwined —> they arise from the same region of intermediate mesoderm and part of the urinary system will be incorporated in the urogenital tract The urinary system is made of the kidney...

Even thought the urinary system and the reproductive system have a functional separation they are anatomically intertwined —> they arise from the same region of intermediate mesoderm and part of the urinary system will be incorporated in the urogenital tract The urinary system is made of the kidneys and the tubing system that serves the purpose of a conduit of urine (pelvicalyceal system, the two ureters, the urinary bladder and the urethra). Difference in females and males —> In females the urethra is quite short and it opens in the vestibule of the vagina while in males it is quite long and it continues in the penis (penile urethra). The fact that in females the urethra is shorter makes it so that females are more susceptible to infections of the urinary bladder than males. In females behind the urethra we can find the vagina and behind it the rectum and anal canal while in males they are directly behind the urethra. The male urethra is surrounded by the prostate gland in the first part and then it continues in the penis (penile urethra) PE c At the level of the prostatic urethra there is the communication with the ductus deferens which is in communication with the epididymis and the seminiferous tubules (seminal fluid will pass through it). The urinary system is made of an upper tract (kidney and ureter) and a lower tract (urinary bladder and urethra) KIDNEY The kidney is the solid organ associated to the urinary system: here the blood is filtered and urine is produced (where all substances that need to be eliminated will be). The functional element of the kidney parenchyma is called nephron (in the kidneys there are millions of nephrons). Each nephron is made of a corpuscle of Malpighi (or renal corpuscle, made of a glomerulo and a Bowman’s capsule), a proximal convoluted tube and a distal convoluted tube, the thick descending portion and the thin descending portion of the loop of Henle, the thin ascending portion and thick ascending portion of the loop of Henle. The distal convoluted tube will then be in communication with the collecting duct. The proximal and distal tubules, loop and collecting duct are collectively called uriniferous tubule. At the level of the nephron: Filtration (to remove particles that can’t be degraded, such as urea) Re absorption (to re absorb the filtered water) Secretion (secretion of other products such as glucose) Excretion (removal of metabolic waste products) DEVELOPMENT OF THE URINARY SYSTEM Everything starts at the level of the intermediate mesoderm, which gives rise to 3 types of kidneys from rostral to caudal one after the other (remnant of the phylogenetic evolution of the kidneys). The first one is the PRONEPHROS, which is not functional (present during 3rd and 4th week), then the MESONEPHROS (or ad interim kidney), which is functional just between the 4th and 8th week (this is the kidney that develops alongside the small intestine and it’s the reason why it has to herniate outside of the abdominal cavity) and finally the METANEPHROS (our functional kidney), which forms at the 5th week from fertilisation and will remain during adult life (functional by the 10th week). tianya.IE During fetal life the kidney does not work as that of an adult but it takes part in the production of amniotic fluid (production of primitive urine). The metanephros develops very caudally while the gonads will develop rostrally, then they will move in the right position The story begins at the 3rd to 4th week in the rostral part of the intermediate mesoderm, which starts differentiating (MTE transition) forming a rod, which grows caudally until it attaches to the cloaca and opens into it. Initially this is a filled tube but then it undergoes cavitation and it becomes hollow —> mesonephric duct of Wolff. The mesoderm close to the mesonephric duct starts to form vesicles or clusters of mesenchymal cells called nephrotomes, which will then form the pronephros and mesonephros. The pronephros regresses rapidly while the vesicles of the mesonephros attached to the mesonephric duct of Wolff will give rise to primordial nephrons (capillaries on one side and duct of Wolff on the other). The mesonephros will function for a while and then start to regress. The mesonephros is also called ad interim kidney or Wolffian body and it occupies most of the abdominal cavity. 2 ie ienIde E i eeboos In the region where the mesonephros forms the gonads will form too (from the urogenital ridge/ crest, which is medial to the mesonephros) I 0 sina.is EE e Right before opening into the cloaca the mesonephric duct of Wolff gives rise to a bud called URETERIC BUD (epithelial bud, MTE transition) which interacts with the mesenchymal cells around it called metanephric mesenchyme as to form the METANEPHROS. So here there is no segmentation of intermediate mesoderm and no nephrotomes or vesicles are formed. If the ureteric bud doesn’t form or the mEEEet forms but doesn’t interact with the mesenchyme (no molecular cross p talk) then the definitive kidney doesn’t develop nephrons From the 5th week the ureteric bud (metanephric diverticulum) will collecting develop into the urine collecting system (ureter, pelvis, minor and major calyces and collecting ducts of the kidneys) while the metanephric mesenchyme will develop into the excretory units (nephrons) The urine collecting system forms through a complex branching mechanism of the ureteric bud —> processes of bifurcation and intussusception (each branch gives rise to other branches and then after a while they intussuscept into one another and then into others again) —> formation of the renal pelvis, the major calyces (2-4), the minor calyces (7-12), the straight collecting tubules and arched collecting tubules. Each minor calyx generates 12-14 orders of bifurcations —> collecting tubules/ducts. The collecting tubules/ducts that drain in a minor calyx form a renal pyramid of Malpighi. The number of pyramids depends on the number of minor calyces. The urine produced by the nephron will be collected by the collecting tubules, which drain into the minor calyces. A lot of the water will then be re absorbed thanks to the stimulation of the ADH in The definite renal architecture of the metanephros is apparent by the 10th week. The parenchyma starts to be organised into renal pyramids (medulla) and cortex Desert animals have a kidney made of just one pyramid to increase surface for water absorption  FORMATION OF THE EXCRETORY UNIT —> the NEPHRON The formation of the nephron requires the interaction between the collecting ducts and the metanephrogenic mesenchyme ET The ureteric bud will give rise to the renal pelvic, which branches in the major calyxes (usually 2 superior, called cephalic major calyxes, and 2 caudal major calyxes), which in turn branch in the minor calyxes, from which straight collecting tubules originate. The straight collecting tubules then give rise to arched collecting tubules, which trigger the condensation of cells of the mesenchyme close to it —> mesenchymal cells form a cap over the tip of the arched tubule, which then arranges into a vesicle (MTE transition). The nephron vesicle will then elongate and eventually come in communication with the arched collecting tubule on the one side and with the capillaries (branches of the renal artery that will then form the glomerulus) on the other side, forming Bowman’s capsule. The glomerulus is made of an afferent and efferent arterioles and in between them there is the cluster of mesenchyme. When tubules branch they might start to intussuscept into the previous ones. Several nephrons drain into a straight collecting tubule/duct. A lobule is a unit made of all the nephrons that drain into a collecting duct NEPHRON Each minor calyx collects urine from a unit of the kidney parenchyma called PYRAMID OF MALPIGHI. Sometimes pyramids may fuse together. The cortical zone above each pyramid bulges on the renal surface and is separated from the others by grooves —> interlobular grooves (not visible in the adult kidney). The regions where the cortex extends in the medulla are called Bertin’s columns (or renal columns) and they delimit the renal pyramids. The corpuscle of Malpighi and the convoluted tubules are NOT located in the renal medulla but in the cortex, while the collecting ducts, arched collecting tubules and initial parts of the loop of Henle are in the medullary region. During the fetal life and in the early stages of post natal life the kidney has a lobulated appearance, but it will soon acquire a smoother appearance Fetheasonfooves mesenchyme uretericbud The ureteric bud growth is depended on some molecular events —> along the length of the mesonephric duct there are many receptors, one of them being Ret. In the region where the ureteric bud is going to form the metanephrogenic mesenchyme (not present in other places along the tube) starts producing a factor called GDNF (glial derived neurotrophic factor), whose receptor is Ret. The mesonephric tube then starts to elongate to reach the mesenchyme drawn by GDNF and the Ret receptors start disappearing along the rest of the tube. Due to genetic problems the ureteric bud might not develop or two of them could develop on one side leading to the formation of more than 2 kidneys The mesenchyme produces a molecule called WT1 which allows it to respond to factors produced by the ureteric bud (such as GDNF and HGF, hepatocyte growth factor). On the side of the epithelium there are receptors for both the GDNF (called Ret) and HGF (called Met). The epithelium also produces FGF2 and BMP7 to induce mesenchymal proliferation and PAX2 and WNT4 to induce the mesenchymal to epithelium differentiation (to form the nephron). Fibronectin and collagen I and III in the mesenchyme are substituted by laminin and collagen IV (typical of the epithelial lamina) to allow the polarisation of the cells (formation of a basal lamina to which the epithelial cells will be attached through hemidesmosomes). This way an apical and a basolateral domain will be created (formation of brush border and lateral junctions). During the 10th to 18th week there is a progressive increase of glomeruli/corpuscles, then there is a rapid increase up until the 32nd week until we reach a stabile situation. At birth we will have 800.000-1.000.000 nephrons per kidney, however there is a huge variability (200.000 to 2.5 millions). This means that different people respond in different ways to pathologies. If you have a few amount of nephrons, when they start to become sclerotic due to aging then your kidneys don’t function well anymore (and it happens way faster than compared to people with a huge amount of nephrons). After birth there is still growth but it only includes the lengthening of the loop of Henle and the growth of the interstitial tissue (not an increase in the number of nephrons). The kidneys start working very early (for the urine to contribute to the amniotic fluid), so glomerular filtration starts around the 9th week of gestation When they form, kidneys are in the sacral region of the body, however in the adult body they are at the level of the 2 lowest ribs, with the right one being a little bit lower due to the growth of the liver. The kidneys are more or less at the level of the duodenum. They kidneys will have to ascend and rotate medially they segesta29k tissue The kidneys are completely RETROPERITONEAL (they’re in the retroperitoneal cavity) 90 Her Initially the kidneys are in the sacral regionbefore and their hilum faces ventrally. Then the kidneys will ascend and rotate so that their hilum faces medially Initially the kidneys are supplied by the common iliac artery, but as they ascend the vessels that were supplying them start to regress. At the same time new arteries will form more rostrally at the level of the abdominal aorta. If one of the most caudal arteries doesn’t regress then the kidneys can’t move up. This regression/genesis process is important both for the blood supply and for the correct positioning of the kidneys. As the kidneys ascend the gonads go down (initially in the region of the mesonephros) WHEN THINGS GO WRONG There can be the formation of SUPERNUMERARY KIDNEYS —> more than one kidneys (maybe two ureteric buds are formed) PELVIC KIDNEY —> one of the kidneys or both don’t ascend due to the non regression of one of the iliac arteries HORSESHOE KDINEY —> both the kidneys don’t ascend —> they get too close to one another and their inferior poles fuse with one another, this way they can’t ascend because they get stuck to the inferior mesenteric artery UNILATERAL RENAL AGENESIS —> only one kidney doesn’t form DIVIDED KIDNEY WITH A BIFID URETER MALROTATION OF THE KIDNEY CROSSED RENAL ECTOPIA —> one kidney goes on the other side instead of ascending straight and ends up fusing with the other kidney DISCOID KIDNEY —> fusion of the kidneys while in the pelvis RENAL and URETERAL DUPLICATIONS Iftheureterisduplicated at an ear stagethenitinteractswiththemesenchy givingrise toanotherkidney These don’t cause problems unless there is a problem with the ureter (kidneys don’t migrate but ureter elongates and folds leading to stagnation of urine) MORE SERIOUS CONDITIONS: Dysplasia —> malformation of the kidney. The more serious it is, the more probable it is that the patient requires dialysis or transplant Renal agenesis —> lack of interaction between the ureteric bud and mesenchyme or non-development of the ureteric bud. This can also be caused by a mutation in the gene for GDNF (which leads to the non interaction between the mesenchyme and the ureteric bud) Bilateral renal agenesis —> it leads to oligohydramnions, the baby is either stillborn or dies after a few days. Oligohydramnions can result in potter syndrome (anuria, hypoplastic lungs, abnormal face, wrinkly and dry skin, limb deformities) Other conditions might result in oligohydramnions—> obstructive uropathy (ureters are not canalised, kidneys work but they can’t release urine in the amniotic fluid), cystic kidney diseases, renal hypoplasia, premature rupture of membranes. Whatever condition that causes oligohydramnions during pregnancy results in Potter syndrome (so it can be caused by one or all of these problems) CONGENITAL POLYCYSTIC KIDNEY DISEASE It can be caused by either genetic or other factors. There are two types: CHILDHOOD Autosomic recessive polycystic kidney disease (ARPKD) —> much quicker, it gives rise to renal failure even in infancy or adolescence. It causes hypertension and might lead to brain haemorrhages. It is given by a mutation of the chromosome 6 (gene PKHD1) and a consequent defective coding of fibrocystin (which is a protein associated to the primary cilium). The cysts might form not only in the kidneys but also in the liver and in the biliary tree as their primary cilium should also express fibrocystin ADULT LIFE Autosomic dominant polycystic kidney disease (ADPKD) —> it proceeds at a slower rate and it leads to renal failure in adult life. It is caused by a mutation in the genes PKD1 and PKD2 and it leads to a defective coding of Policystin 1 and 2, which leads to the abnormal elongation and maturation of the primary cilium. Cysts can be found in the nephrons, the liver, pancreas, testis and ovaries. CONGENITAL HYDRONEPHROSIS: Something causes an impairment of the flow of urine —> usually caused by ureter obstruction —> urine starts to stagnate in the renal pelvis, which starts to dilate (alongside the major and minor calyxes). The pressure starts to build up and compresses the kidney parenchyma. The kidneys work well in the first place, the problem is in the conductive system. The obstruction can be caused by: bending of the junction between the pelvis and the ureter (urine struggles to pass to the ureter), compression by an aberrant vessel (maybe one of the caudal arteries doesn’t regress and constricts the ureter, or a new vessel originates), anomalies in the development of the ureteric bud (the correct process of canalisation doesn’t take place). WILMS TUMOUR or NEPHROBLASTOMA Blastoma = tumour caused by remnants of things that should regress over embryological development. It is the most common childhood abdominal malignancy (usually detected in 3.5 yo kids). Approximately 80-90% of kids with this tumour survive. The cause is not precisely known but in 10-15% of cases it is due to a mutation in the tumour suppressor gene WT1 (if suppressed there is a downregulation of E-cadherins which leads to the loss of cell-cell adhesion junctions and thus to epithelia to mesenchymal transition) while in then rest of the cases it due to persistent metanephric tissue or nephrogenic remnants. Wilms tumour is mass that seems to recapitulate the different stages of development of the kidney. The tumour might metastasise, mainly in the respiratory system bloodinurine the festmight hematuria yqsaetsaeembe.geteess c micro 2 getfierce DEVELOPMENT OF THE BLADDER AND URETHRA - the cloaca In the cloaca there is the formation of the urorectal septum, which gives rise to an anterior compartment (urogenital sinus, in continuity with the allantois) and a dorsal portion (associated to the last part of the digestive tube, anal canal). The cloacal membrane is divided by the septum as well The superior part of the urogenital sinus (in continuous with the allanotis) will form the urinary bladder, while the inferior part will form the urethra. The distal expansion of the urogenital sinus forms the vestibule of the vagina in females and the penile urethra in males. Around the male urethra the prostate gland will form —> the endoderm will give rise to tiny evaginations surrounded by mesenchyme than will assemble as to form the prostate gland  If the partitioning of the cloaca into the urogenital sinus and the anorectal canal is very complex and can be defective —> RECTO-BLADDER NECK FISTULA and RECTO-URETHRAL FISTULA The distal portion of the mesonephric duct and the ureteric bud are incorporated in the posterior wall of the urogenital sinus (where there is the communication with the cloaca). Thanks to this, the ureteric bud and the mesonephric duct open independently on the cloaca (before the ureteric bud had to pass through the mesonephric duct). Thanks to this incorporation there is the formation of the bladder trigone (triangular region of the urinary bladder, it has a different embryological region from the rest of the bladder because it doesn’t originate from the endoderm of the ureteric bud but from the mesoderm of the mesonephric duct). The ureters open rostrally in the region of the future bladder. The mesonephric ducts initially communicate with the caudal part of the urogenital sinus (where the urethra will form), but then something else will happen: In males —> the mesonephric duct will transform into the ductus deferens, seminal vesicles and the epididymis (genital system) In females —> the mesonephric duct regresses  0 the ifeng.FI renren.me ffqae ifeng.fi QEEEIighdfgiese.eu The allantois will regress and form the URACHUS —> fibrous cord In the adult, the urachus will form the MEDIAN UMBILICAL LIGAMENT (one of the ligaments of the urinary bladder, it is medial because the allantois was medial) Something can go wrong in the process of obliteration of the urachus —> URACHUS ANOMALIES: Urachal cysts Urachal sinus —> small opening at the level of the umbilicus from a communication with the bladder (leakage of liquids, not urine, from the umbilicus like with the Meckel’s diverticulum) Patent urachus or urachal fistula —> full communication between the urinary bladder and the umbilicus (urine comes out from the umbilicus)  EXSTROPHY OF THE BLADDER Defect most likely due to a problem in the migration of the mesenchyme between the ectoderm and the endoderm at the level of the anterior abdominal wall If the mesoderm doesn’t migrate correctly then the endoderm of the cloaca can’t communicate correctly with the mesoderm. The baby is born with an incomplete abdominal wall and the bladder is exposed and OPEN (you can see the inside of the bladder). Since the urogenital sinus also gives rise to the genital system and the urethra then those won’t form correctly as well. There will be a major evisceration mucosaofthe inside This is usually associated to epispadia —> defects in the formation of the penile urethra Hypospadia = urethra isn’t complete in some places DORSALLY Epispadia = urethra isn’t complete in some places VENTRALLY DEVELOPMENT OF THE GENITAL SYSTEM Outline of the adult male reproductive system: Gonads (testis, outside of the body) —> seminiferous tubules - straight tubules - rete testis - ductuli efferentes - epididymis (one single very convoluted tube) - ductus deferens Prostatic urethra (inside the pelvis) —> the ductus deferens renters the body through the inguinal canal and connects to the prostatic urethra Membranous urethra Spongeous urethra Penile urethra Outline of the adult female genital system: Gonads (ovaries, inside the body) Fallopian tubes Uterus Vagina More rudimental inguinal canal Medial to the mesonephros there will be the appearance of a protrusion: the UROGENITAL RIDGE. The urogenital ridge is the result of a bilateral thickening of the ventrolateral surface of the mesonephros. In males in this region there is also the development of the adrenal gland The genital ridge is formed by the mesenchyme of the intermediate mesoderm and by the contribution of the coelomatic mesothelium that will line the future peritoneal cavity, which protrudes inside the mesenchyme. ON MIGRATIONOFGERMCEUS INTERACT The primitive gonad is organised into a more superficial region, called cortex, and a medulla. The cells of the mesothelium start proliferating and arranging in clusters forming the primitive sex cords (or gonadal cords), which will then be colonised by PGCs. The support cells of the gonads (follicular cells, Sertoli cells, Leydig cells…) will originate from the cells of the gonadal cords. Primordial germ cells will reach the gonads travelling through the yolk sac and dorsal mesentery (5-6th week) Until the 6th week the gonads are still INDIFFERENT —> they looks the same in males and females. Close to the developing gonad there is the mesonephric tube —> some of the mesonephric tubules will anastomose (connect) with the gonadal cords of the medulla. The tubules that will anastomose with the gonadal cords will have a different destiny depending on wether we’re in a male or female. Those that won’t connect to the gonadal cords will regress While the mesonephric tubules connect with the gonadal cords the paramesonephric duct of Müller originates. The paramesonephric duct originates from the invagination of the coelomic epithelium. In females, CAUDALLY, the two paramesonephric ducts will come together and come in contact with the future urethra, ROSTRALLY, the paramesonephric ducts will open in the coelomic cavity close to the gonads, forming the fallopian tubes The paramesonephric duct will give rise to the fallopian tube, uterus and upper part of the vagina. However, up to the 6th week the gonad remains indifferent FEMALE GONAD In females the gonadal cords of the medullary portion will degenerate and as a consequence the connection with the mesonephros (through the mesonephric tubules) is lost. On the other hand the gonadal cords of the cortex will start to break down into isolated cell clusters (will contribute to the formation of the primordial follicle surrounding oogonia). In females the mesonephric tubules and ducts will degenerate (might give rise to remnants that lead to the formation of cysts very close to the vagina, Gartner’s cysts)  MALE GONAD The medullary cords remain and so the connection with the mesonephric tubules is maintained. These mesonephric tubules will then form the rete testis and the ductuli efferentes which will then be connected to the epididymis (evolution of the mesonephric duct). At puberty the medullary cords will canalise and from the seminiferous tubules (connection with the rete testis). The cortical cords on the other hand will degenerate and form the tunica albuginea (outermost layer of the testis, made of CT). Remnants of the paramesonephric ducts will form the prostatic utricle The gonad by default is a female gonad, but if we are in a genetic male (presenting Y chromosome) at the level of the Y chromosome there is a gene called SRY (sex determining region of the Y chromosome) which starts coding for a protein —> the support cells (pre Sertoli cells) will start producing a protein which will lead to the formation of Sertoli cells. Then the Sertoli cells start producing factors that trigger the formation of Leydig cells. Leydig cells will then start producing hormones (testosterone) which will act on the mesonephric duct allowing it to survive and differentiate into epididymis, ductus deferens and seminal vesicles. Testosterone is en brought to the periphery, where it is transformed into dihydrotestosterone by 5α-reductase and stimulates the formation of the prostate, scrotum and penis. The paramesonephric duct will degenerate due to the secretion of Müllerian inhibiting factor by Sertoli cells (which is still produced in the adult but for the maturation of spermatozoa). Fetal Leydig cells will then become quiescent and then another generation of them will awake during puberty and lead to the canalisation of the gonadal cords, giving rise to the seminiferous tubules. Sertoli cells at this stage also start producing androgen binding factor (which binds to testosterone to keep it in the gonads) thanks to which the canalisation of the seminiferous tubules will take place (not enough testosterone in the gonads = no canalisation) In females the SRY is absent, so primordial cells undergo their first meiotic division thus committing to the oocyte lineage. The mesonephric duct regresses while the paramesonephric remains (no Sertoli cells = no Leydig and ABP and no anti-Müllerian hormone). Remnants of the mesonephric duct are called epoöphoron while those of the mesonephric tubules are called paroöphoron TIMELINE OF PHENOTYPIC SEXUAL DIFFERENTIATION Week 7 —> beginning By week 12 —> female or male characteristics of external genitalia can be recognised By week 20 —> phenotypic differentiation complete PARAMESONEPHRIC DUCT OF MÜLLER in females The distal portions of the the paramesonephric ducts come in relationship with the endoderm of the urogenital sinus and fuse to form the uterus. The two non- fused proximal parts will form the fallopian tubes close to the future ovaries. In the region where they come into contact there is the formation of a thickening called uterovaginal plate, which elongates extending towards the most caudal part of the urethra until it reaches a complete separation from it, leading to the independent opening of the vagina. The É vagina has a DOUBLE ORIGIN —> upper part of the vagina originates from the paramesonephric duct while the lower from the urogenital sinus if RECTO-VAGINAL AND RECTO-VESTIBULAR FISTUALAE Recto-vaginal —> communication between vagina and rectum —> meconium comes out of the vagina Recto-vestibular —> communication between the vestibule of the vagina and the rectum. There is one common opening clovaginal UTERINE MALFORMATIONS Sometimes the process of fusion between the two paramesonephric tubes doesn’t take place correctly and the uterus doesn’t form correctly —> impossibility of bearing a child in adult life UTERUS DIDELPHYS (or uterus duplex separatus, completely detached) UTERUS DUPLEX BICORNIS (they manage to come together but the septum remains) UTERUS BICORNIS UNICOLLIS (they converge as to form one neck but the upper part is still separated) When the urogenital crests swing to get the paramesonephric ducts together the peritoneum is lifted and the broad ligament of the uterus is formed. The gonads then need to DESCEND and in the male individual they have to exit the abdominal cavity (temperature reasons). This process implies the formation of a canal, called INGUINAL CANAL (as it forms in the inguinal region). It is a canal that provides a communication between the abdominal cavity and the perineum (where the scrotal bursa will form in males and the labia majora in females). This conduit in males is a passageway for the gonads (as they’re located outside of the body). In males the inguinal canal will contain the ductus deferens, vessels and nerves directed to the testis and to the inguinal area. In females the canal is more rudimentary and it contains the round ligament of the uterus and nerves (no vessels because there are no gonads to supply). With the formation of the inguinal canal and descent of the gonads some layers of the abdominal cavity will be brought outside as to form an extroflexion. This extroflexion will then form the scrotum (skin, subcutaneous tissue, external spermatic fascia, cremaster muscle, cremasteric fascia, internal spermatic fascia and tunica vaginalis, made of a visceral and a parietal layer) DESCENT OF THE GONADS In males they go outside of the abdominal cavity, in the scrotal bursa In females they go in the true pelvis The urogenital ridge is attached above (to the diaphragm ) by the cranial suspensory ligament while below to the floor of the abdominal cavity (where the labioscrotal swellings are forming) by the gubernaculum (caudal suspensory ligament) Medial to the gubernaculum the peritoneum that covers the abdominal wall starts pushing against the inferior portion of the abdominal wall, forming an out-pocketing called processus vaginalis. This process will lead to the formation of the inguinal canal.  The gubernaculum starts shortening and as a consequence the testis are pulled in the inguinal canal. Trans-abdominal phase —> testis are still in the abdomen, they’re just descending (finished by the 25th week of gestation, very leisurely) Trans-inguinal phase —> phase in which the testis stay in the inguinal canal (only lasts 2-3 days) By the 32nd week is are in the scrotum The communication between the processus vaginalis and the peritoneal cavity then has to disappear (otherwise the very mobile small intestine could slide into the scrotal bursa) so the proximal portion of the processus vaginalis regresses. The distal portion will instead remain and form the tunica vaginalis CRYPTOTORCHIDISM (or undescended testis) Testis remain stuck in certain places (either on the trajectory followed during the process of migration, green, or in completely different places, blue). This is a problem in terms of temperature and so it causes sterility  When the communication is obliterated the tunica vaginalis remains (remnant of peritoneal evaginations). However it can happen that during the process of obliteration cysts form due to fluid accumulation (FLUID-FILLED CYST or HYDROCELE). It can also happen that the communication is not obliterated at all and then an INDIRECT INGUINAL HERNIA might occur (since the intestine is very mobile it can herniate in the inguinal canal). This can lead to problems in the intestine, which might be constricted (—> ischemic). Inguinal hernia can be divided into direct and indirect DESCENT OF THE GONADS IN FEMALES The inguinal canal is rudimentary. The gubernaculum here shortens very little and attaches to the paramesonephric duct while the paramesonephric duct is forming the uterus and the uterine tubes (impossible in the males because the paramesonephric duct regress). The site of attachment divides into the round ligament of the uterus and the round ligament of the ovary Caudally the round ligament of the uterus crosses the inguinal canal and attaches to the future labia majora The ovaries descend a bit (3rd month) and are swept in a fold of peritoneum called broad ligament of the uterus  peeingthe DEVELOPMENT OF THE ADRENAL GLAND Medial to the gonad there is a condensation of mesenchyme that will then give rise to the adrenal gland. The cortex of the adrenal gland originates from a proliferation of coelomatic epithelium in the mesenchyme of the genital ridge, while the medullary region originates from the migration of neural crest cells. The medullary portion is like a ganglion of the parasympathetic nervous system, and since the parasympathetic nervous system originates from the neural crest cells then also the medulla originates from there. The proliferation of the coelomic epithelium takes place in two steps —> first wave of migration = formation of the fetal cortex. Second wave of migration = future adult cortex The fetal cortex sustains pregnancy and produces factors that help lung, liver and digestive tract maturation. During the 2nd trimester the fetal cortex produces Dehydroepiandrosterone (hormonal precursor) which reaches the placenta and is converted into estradiol (important for maintaining pregnancy). The fetal cortex regresses during the second post-natal month while the adult cortex is maturing. WHEN THINGS GO WRONG NEUROBLASTOMA: it is a malignant tumour of the PNS deriving from neural crest cells and in 40% of cases it is present in the adrenal medulla (neural crest cells remain undifferentiated and start proliferating, arranging themselves in Homer-Wright pseudo-rosettes). It is the most common and deadly extracranial tumour in childhood. In 60% of cases it develops in sympathetic ganglia. It can metastasise to bones and lymph nodes. DEVELOPMENT OF THE EXTERNAL GENITALIA During the fourth week mesenchymal cells migrate around the cloacal membrane and create the urogenital folds (or urethral folds or cloacal folds). The cranial fusion of the folds will form the genital tubercle. The folds will then be divided (alongside the cloacal membrane) in a urethral portion and anal portion. On the sides of the urethral folds we will find the labioscrotal swellings (in females they will form the labia majora while in males the scrotal bursa) IN FEMALES The elongation of the genital tubercle forms the clitoris, the urethral folds don’t fuse and form the labia minora, the labioscrotal swellings will form the labia majora and the urethral groove will remain open and be the vestibule of the vagina (where we have the opening of the vagina and of the urethra) IN MALES The rapid elongation of the genital tubercle forms the phallus and the glans of the penis, the phallus pulls the urethral folds forming the urethral groove. By the end of the 3rd month the urethral folds fuse and form the penile urethra. An ectodermal cord contributes to the formation of the external urethral meatus (tip of the penis). The genital swellings become the scrotal swellings and form the scrotum HYPOSPADIAS Presence of one or more abnormal openings of the urethra along the dorsal face of the penis. This is a result of incomplete closure of the urethral folds during development. Surgery is usually performed to correct the defect.