The  arteries  that supply the ureters end in a network of vessels within the  adventitia  of the ureters. [ 1 ]  There are many connections ( anastamoses ) between the arteries of the ureter, [ 2 ]  particularly in the adventitia, [ 5 ]  which means damage to a single vessel does not compromise the blood supply of the ureter. [ 2 ] [ 5 ]  Venous drainage mostly parallels that of the arterial supply; [ 5 ] [ 2 ]  that is, it begins as a network of smaller veins in the adventitia; with the renal veins draining the upper ureters, and the vesicular and gonadal veins draining the lower ureters. [ 1 ]


Lymphatic drainage depends on the position of lymphatic vessels in the ureter. [ 1 ]   Lymph  collects in submucosal, intramuscular and adventitial  lymphatic vessels . [ 2 ]  Those vessels closer to the kidney drain into renal collecting vessels, and from here into the  lateral aortic nodes  near the gonadal vessels. [ 2 ]  The middle part of the ureter drains into the right paracaval and interaortocaval nodes on the right, and the left paraaortic nodes on the left. [ 1 ]  In the lower ureter, lymph may drain into the  common iliac lymph nodes , or lower down in the pelvis to the  common ,  external , or  internal iliac lymph nodes . [ 2 ]


The ureters are richly supplied by nerves that form a network ( plexus ) of nerves, the  ureteric plexus  that lies in the adventitia of the ureters. [ 2 ]  This plexus is formed from a number of  nerve roots  directly (T9–12, L1, and S2-4), as well as branches from other nerve plexuses and nerves; specifically, the upper third of the ureter receives nerve branches from the  renal plexus  and  aortic plexus , the middle part receives branches from the upper  hypogastric plexus  and  nerve , and the lower ureter receives branches from the lower hypogastric plexus and nerve. [ 2 ]  The plexus is in the adventitia. These nerves travel in individual bundles and along small blood vessels to form the ureteric plexus. [ 2 ]  Sensation supplied is sparse close to the kidneys and increases closer to the bladder. [ 2 ]


Sensation to the ureters is provided by nerves that come from T11 – L2 segments of the  spinal cord . [ 2 ]  When pain is caused, for example by spasm of the ureters or by a stone, the  pain may be referred  to the  dermatomes  of T11 – L2, namely the back and sides of the abdomen, the scrotum (males) or labia majora (females) and upper part of the front of the thigh. [ 2 ]


The ureter is lined by  urothelium , a type of  transitional epithelium  that is capable of responding to stretches in the ureters. The transitional epithelium may appear as a layer of  column-shaped cells  when relaxed, and of  flatter cells  when distended. Below the epithelium sits the  lamina propria . The lamina propria is made up of loose connective tissue with many elastic fibers interspersed with blood vessels, veins and lymphatics. The ureter is surrounded by two muscular layers, an inner longitudinal layer of muscle, and an outer circular or spiral layer of muscle. [ 6 ] [ 7 ]  The lower third of the ureter has a third muscular layer. [ 7 ]  Beyond these layers sits an  adventitia  containing blood vessels, lymphatic vessels, and veins. [ 7 ]


The ureters develop from the  ureteric buds , which are outpouchings from the  mesonephric duct . This is a duct, derived from  mesoderm , found in the early  embryo . [ 8 ]  Over time, the buds elongate, moving into surrounding mesodermal tissue, dilate, and divide into left and right ureters. Eventually, successive divisions from these buds form not only the ureters, but also the pelvis, major and minor calyces, and collecting ducts of the kidneys. [ 8 ]


The mesonephric duct is connected with the  cloaca , which over the course of development splits into a  urogenital sinus  and the  anorectal canal . [ 8 ]  The urinary bladder forms from the urogenital sinus. Over time, as the bladder enlarges, it absorbs the surrounding parts of the primitive ureters. [ 8 ]  Finally, the entry points of the ureters into the bladder move upwards, owing to the upward migration of the kidneys in the developing embryo. [ 8 ]


The ureters are a component of the  urinary system .  Urine , produced by the kidneys, travels along the ureters to the bladder. It does this through regular contractions called  peristalsis . [ 2 ]


A  kidney stone  can move from the  kidney  and become lodged inside the ureter, which can block the flow of urine, as well as cause a sharp  cramp  in the back, side, or lower  abdomen . [ 9 ]  Pain often comes in waves lasting up to two hours, then subsides, called  renal colic . [ 10 ]  The affected kidney could then develop  hydronephrosis , should a part of the kidney become  swollen  due to blocked flow of urine. [ 9 ]  It is classically described that there are three sites in the ureter where a kidney stone will commonly become stuck:
where the ureter meets the renal pelvis; where the iliac blood vessels cross the ureters; and where the ureters enter the urinary bladder, [ 9 ]  however a  retrospective   case study , which is a  primary source , of where stones lodged based on  medical imaging  did not show many stones at the place where the iliac blood vessels cross. [ 11 ]


Most stones are compounds containing  calcium  such as  calcium oxalate  and  calcium phosphate . The first recommended investigation is a  CT scan of the abdomen  because it can detect almost all stones. Management includes  analgesia , often with  nonsteroidal antiinflammatories . [ 10 ]  Small stones (< 4mm) may pass themselves; larger stones may require  lithotripsy , and those with complications such as hydronephrosis or infection may require surgery to remove. [ 10 ]


Vesicoureteral reflux  refers to the reflux of fluid from the bladder into the ureters. [ 12 ]  This condition can be associated with  urinary tract infections , particularly in children, and is present in up to 28–36% of children to some degree. [ 12 ]  A number of forms of medical imaging are available for diagnosis of the condition, with modalities including  doppler   urinary tract ultrasound .Factors that affect which of these are selected depends if a child is able to receive a  urinary catheter , and whether a child is  toilet trained . [ 12 ]  Whether these investigations are performed at the first time a child has an illness, or later and depending on other factors (such as if the causal bacteria is  E. coli ) differ between US, EU and UK guidelines. [ 12 ]


Management is also variable, with differences between international guidelines on issues such as whether  prophylactic antibiotics  should be used, and whether surgery is recommended. [ 12 ]  One reason is most instances of vesicoureteral reflux improve by themselves. [ 12 ]  If surgery is considered, it generally involves reattaching the ureters to a different spot on the bladder, and extending the part of the ureter that it is within the wall of the bladder, with the most common surgical option being Cohen's cross-trigonal reimplantation. [ 12 ]


Blockage, or obstruction of the ureter can occur, [ 13 ]  as a result of narrowing within the ureter, or compression or fibrosis of structures around the ureter. [ 14 ]  Narrowing can result of ureteric stones, masses associated with cancer, and other lesions such as  endometriosis   tuberculosis  and  schistosomiasis . [ 14 ]  Things outside the ureters such as  constipation  and  retroperitoneal fibrosis  can also compress them. [ 14 ]  Some  congenital abnormalities  can also result in narrowing or the ureters. Congenital disorders of the ureter and  urinary tract  affect 10% of infants. [ 13 ]  These include partial or total duplication of the ureter (a  duplex ureter ), or the formation of a second irregularly placed ( ectopic ) ureter; [ 13 ]  or where the junction with the bladder is malformed or a  ureterocoele  develops (usually in that location). [ 14 ]  If the ureters have been resited as a result of surgery, for example due to a  kidney transplant  or due to past surgery for vesicoureteric reflux, that site may also become narrowed. [ 15 ] [ 1 ]


A narrowed ureter may lead to ureteric enlargement ( dilation ) and cause swelling of the kidneys ( hydronephrosis ). [ 13 ]  Associated symptoms may include recurrent infections, pain or  blood in the urine ; and when tested,  kidney function  might be seen to decrease. [ 13 ]  These are considered situations when surgery is needed. [ 13 ]  Medical imaging, including urinary tract ultrasound,  CT  or  nuclear medicine  imaging is conducted to investigate many causes. [ 13 ] [ 14 ]  This may involve reinserting the ureters into a new place on the bladder (reimplantion), or widening of the ureter. [ 13 ]  A  ureteric stent  may be inserted to relieve an obstruction. [ 16 ]  If the cause cannot be removed, a  nephrostomy  may be required, which is the insertion of a tube connected to the renal pelvis which directly drains urine into a  stoma bag . [ 17 ]


Cancer  of the ureters is known as  ureteral cancer . It is usually due to cancer of the urothelium, the cells that line the surface of the ureters. Urothelial cancer is more common after the age of 40, and more common in men than women; [ 18 ]  other risk factors include  smoking  and exposure to  dyes  such as  aromatic amines  and  aldehydes . [ 18 ]  When cancer is present, the most common symptom is blood in the urine; it may not cause symptoms, and a physical  medical examination  may be otherwise normal, except in late disease. [ 18 ]  Ureteral cancer is most often due to cancer of the cells lining the ureter, called  transitional cell carcinoma , although it can more rarely occur as a  squamous cell carcinoma  if the type of cells lining the urethra have changed due to chronic inflammation, such as due to stones or schistosomiasis. [ 18 ]


Investigations performed usually include collecting a sample of urine for an inspection for malignant cells under a microscope, called  cytology , as well as medical imaging by a CT urogram or  ultrasound . [ 18 ]  If a concerning lesion is seen, a flexible camera may be inserted into the ureters, called  ureteroscopy , in order to view the lesion and take a  biopsy , and a  CT scan  will be performed of other body parts (a  CT scan of the chest, abdomen and pelvis ) to look for additional  metastatic  lesions. [ 18 ]  After the cancer is  staged , treatment may involve  open surgery  to remove the affected ureter and kidney if it is involved; or, if the lesion is small, it may be removed via ureteroscopy. [ 18 ]  Prognosis can vary markedly depending on the  tumour grade , with a worse prognosis associated with an ulcerating lesion. [ 18 ]


Injuries to the ureter can occur after penetrating abdominal injuries, and injuries at high speeds followed by an abrupt stop (such as a high speed car accident). [ 19 ]  The ureter can be injured during surgery to nearby structures. [ 20 ]  It is injured in 2 per 10,000 cases of vaginal  hysterectomies  and 13 per 10,000 cases of  abdominal hysterectomies , [ 20 ]  usually near the  suspensory ligament of the ovary  or near the  cardinal ligament , where the ureter runs close to the  blood vessels of the uterus . [ 21 ]


Several forms of medical imaging are used to view the ureters and urinary tract. [ 22 ]  Ultrasound may be able to show evidence of blockage because of hydronephrosis of the kidneys and renal pelvis. [ 22 ]  CT scans, including ones where  contrast media  is injected  intravenously  to better show the ureters, and with contrast to better show lesions, and to differentiate benign from malignant lesions. [ 22 ]  Dye may also be injected directly into the ureters or renal tract; an  antegrade pyelogram  is when contrast is injected directly into the renal pelvis, and a  retrograde pyelogram  is where dye is injected into the urinary tract via a catheter, and flows backwards into the ureters. [ 22 ]  More invasive forms of imaging include ureteroscopy, which is the insertion of a flexible  endoscope  into the urinary tract to view the ureters. [ 23 ]  Ureteroscopy is most commonly used for medium to large-sized stones when less invasive methods of removal cannot be used. [ 23 ]


All  vertebrates  have two kidneys located behind the abdomen that produce urine, and have a way of excreting it, so that waste products within the urine can be removed from the body. [ 24 ]  The structure specifically called the ureter is present in  amniotes , meaning  mammals ,  birds  and  reptiles . [ 24 ]  These animals possess an adult kidney derived from the  metanephros . [ 24 ]  The duct that connects the kidney to excrete urine in these animals is the ureter. [ 24 ]  In  placental mammals , it connects to the  urinary bladder , whence urine leaves via the  urethra . [ 25 ]  In  monotremes , urine flows from the ureters into the  cloaca . [ 26 ]  The ureters are  ventral  to the  vasa deferentia  in male placental mammals, but dorsal to the vasa deferentia in  marsupials . [ 27 ]  In female marsupials, the ureters pass between the median and lateral  vaginae . [ 28 ]


The word "ureter" comes from the  Ancient Greek  noun  οὖρον ,  ouron , meaning "urine", and the first use of the word is seen during the era of  Hippocrates  to refer to the  urethra . [ 29 ]  The anatomical structure of the ureter was noted by 40 AD. However, the terms "ureter" and "urethra" were variably used to refer to each other thereafter for more than a millennium. [ 29 ]  It was only in the 1550s that anatomists such as  Bartolomeo Eustachi  and  Jacques Dubois  began to use the terms to specifically and consistently refer to what are in modern English called the ureter and the urethra. [ 29 ]  Following this, in the 19th and 20th centuries, multiple terms relating to the structures such as  ureteritis  and ureterography, were coined. [ 29 ]


Kidney stones have been identified and recorded about as long as written historical records exist. [ 30 ]  The urinary tract including the ureters, as well as their function to drain urine from the kidneys, has been described by  Galen  in the second century AD. [ 31 ]


The first to examine the ureter through an internal approach, called ureteroscopy, rather than surgery was  Hampton Young  in 1929. [ 30 ]  This was improved on by  VF Marshall  who is the first published use of a flexible endoscope based on  fiber optics , which occurred in 1964. [ 30 ]  The insertion of a drainage tube into the renal pelvis, bypassing the ureters and urinary tract, called nephrostomy, was first described in 1941. Such an approach differed greatly from the open surgical approaches within the urinary system employed during the preceding two millennia. [ 30 ]


The first  radiological imaging  of the ureters was by  X-rays , although this was made more difficult by the thick abdomen, which the low power of the original X-rays could not penetrate enough to produce clear images. [ 32 ]  More useful images were able to be produced when  Edwin Hurry Fenwick  in 1908 pioneered the use of tubes covered in  radioopaque  material visible to X-rays inserted into the ureters, and in the early 20th century when contrasts were injected externally into the urinary tract (retrograde pyelograms). [ 32 ]  Unfortunately, much of the earlier retrograde pyelograms were complicated by significant damage to the kidneys as a result of contrast based on  silver  or  sodium iodide . [ 32 ]  Hryntshalk in 1929 pioneered the development of the  intravenous urogram , in which contrast is injected into a vein and highlights the kidney and, when excreted, the urinary tract. [ 32 ]  Things improved with the development by  Moses Swick  and  Leopold Lichtwitz  in the late 1920s of relatively nontoxic contrast media, with controversy surrounding publication as to who was the primary discoverer. [ 32 ]  Side-effects associated with imaging improved even more when  Tosten Almen  published a ground-breaking thesis in 1969 based on the less toxic low-osmolar contrast media, developed based on swimming experiences in lakes with different salinity. [ 32 ]


A  urethral bulking injection  is a gynecological procedure and medical treatment used to treat involuntary leakage of urine: urinary incontinence in women. Injectional materials are used to control stress incontinence. Bulking agents are injected into the mucosa surrounding the bladder neck and proximal urethra. This reduces the diameter of the urethra and creates resistance to urine leakage. After the procedure, the pressure forcing the urine from the bladder through the urethra is resisted by the addition of the bulking agent in the tissue surrounding the proximal urethra. Most of the time this procedure prevents urinary stress incontinence in women.


A urethral bulking injection is one type of treatment for  incontinence  in women. Urethral bulking injections are considered by a  clinician  when the woman has  urinary sphincter  dysfunction,  urethral hypermobility , persistent stress urinary incontinence after a  urethral sling  or urethropexy, or stress urinary incontinence in women who cannot undergo surgery due to other illnesses or conditions. It restores the ability to retain urine during coughing, laughing and other normal occurrences that increase inter-abdominal pressure [ 1 ]  Some women choose to have urethral bulking injections because they wish to avoid surgery or the use of mesh material. Another reason other treatments may not be chosen include the desire to maintain fertility. Woman who benefit most from this treatment are those who have a stable bladder neck and an inadequate muscle strength of the sphincter muscles that close the urethra. Urethral instability is identified by the angle of the urethra. This can be evaluated when the woman lies on her back and the angle of the urethral is greater than 30° during coughing. Tests are performed to confirm the diagnosis of stress urinary incontinence such as the bladder capacity to hold urine and the strength of the bladder muscle contractions. [ 2 ]


Diagnosis is aided before the procedure by a thorough evaluation of the woman. Information that is gathered prior to the injection includes consists of a medical history and physical exam. The residual, postvoid residual urine determination and urinalysis and urine culture help in the diagnosis. The surgeon will ask the woman to keep a diary of urine output and frequency. The physician may order a urodynamic evaluation to establish the diagnosis of intrinsic sphincter deficiency. A voiding diary and/or a measured voided volume gives an estimate of bladder capacity. A free-flow uroflowmetric examination gives additional information about flow rate, voided time and volume. A cystometrogram will evaluate detrusor over-activity, bladder compliance, bladder capacity, and abdominal (Valsalva) leak pressure. Another diagnostic tool is the urethral pressure profile. This measures the maximum urethral closure strength. The physician will use instrumentation and do a visual examination called a urethroscopic visualization. [ 2 ]


A woman may not be a good candidate for the procedure. Contraindications for this treatment are having a current urinary tract infection, having difficulty emptying the bladder, having a urethral stricture, having a urethral obstruction or having fragile or sensitive tissue where the injections are to be placed. In some women, cancer treatments may have created changes in the urethra, bladder and sphincter muscles which would prevent the success of the treatment. [ 2 ]


These are the most popular urethral bulking agents in the United States [ as of? ]  now that Contigen is no longer available. The ideal bulking material should be non allergic, tissue friendly, not migrate and be long-lasting. However, this has not been found, and despite a prolonged search, nothing financially feasible as yet appeared to be better than the available bulking agents. Urolastic is a new injectable product that seems to be a good candidate to become the ideal product for a minimal invasive and outpatient treatment of stress urinary incontinence since it is not degraded by the body and maintains form. [ citation needed ]


Urethral bulking agents were first used in 1938 and incorporated morrhuate sodium as the injection material. Bovine collagen use began after 1989 and was considered the best example of treatment. All subsequent studies afterwards were compared with this agent. Its use was stopped in 2011. Other bulking agents have been in use since the 1990s. The use of some was discontinued due to complications, the 'unpleasantness' of the procedure and the cost of the procedure. [ 2 ]


Improved materials continue to be investigated. A successful bulking agent should be readily available, non-inflammatory, easy to inject, easy to prepare, efficacious, durable, inexpensive, biocompatible, nonimmunological, long-lasting, non-migrating (the size of the particles should be larger than 80 μm)   adult stem cell injection therapy using autologous muscle-derived stem cells for the regenerative repair of an impaired sphincter is currently at the forefront of incontinence research. The implanted cells fuse with muscle and release trophic factors promoting nerve and muscle integration. Small pilot studies have suggested restoration of the urethral sphincter over several months' time. [ 2 ]


The  urethral sphincters  are two  muscles  used to control the exit of  urine  in the  urinary bladder  through the  urethra . The two muscles are either the  male  or  female external urethral sphincter  and the  internal urethral sphincter . When either of these muscles contracts, the  urethra  is sealed shut.


The external urethral sphincter originates at the  ischiopubic ramus  and inserts into the intermeshing muscle fibers from the other side. It is controlled by the deep perineal branch of the   pudendal nerve .  Activity in the nerve fibers constricts the urethra.


In males and females, both  internal  and external urethral sphincters function to prevent the release of urine. The internal urethral sphincter controls involuntary urine flow from the bladder to the urethra, whereas the external urethral sphincter controls voluntary urine flow from the bladder to the urethra. [ 2 ]  Any damage to these muscles can lead to  urinary incontinence . In males, the internal urethral sphincter has the additional function of preventing the flow of  semen  into the male bladder during  ejaculation . [ 3 ]


Females do have a more elaborate external sphincter muscle than males as it is made up of three parts: the sphincter urethrae, the urethrovaginal muscle, and the compressor urethrae. The urethrovaginal muscle fibers wrap around the vagina and urethra and contraction leads to constriction of both the vagina and the urethra. The origin of the compressor urethrae muscle is the right and left  inferior pubic ramus  and it wraps anteriorly around the urethra so when it contracts, it squeezes the urethra against the vagina. The external urethrae, like in males, wraps solely around the urethra. [ 4 ]


Congenital abnormalities of the female urethra can be surgically repaired with  vaginoplasty . [ 5 ]


The urethral sphincter is considered an integral part of maintaining  urinary continence , and it is important to understand its role in some conditions:


The  urinary meatus [ a ]  ( / m iː ˈ eɪ t ə s / ,  mee- AY -təs ;  pl. :  meati  or  meatuses ), also known as the  external urethral orifice , is the opening of the  penis  or  vulva  where  urine  exits the  urethra  during  urination . It is also where  semen  exits during male  ejaculation , and other fluids during  female ejaculation . The meatus has varying degrees of sensitivity to touch.


The male external urethral orifice is the external opening of the urethra, normally located at the tip of the  glans penis , [ 1 ]  at its junction with the  frenular delta . It presents as a vertical slit, possibly bounded on either side by two small labia-like projections, and continues longitudinally along the front aspect of the glans, which facilitates  micturition . In some cases, the opening may be more rounded. This can occur naturally or may also occur as a side effect of excessive skin removal during circumcision. The meatus is a sensitive part of the  male reproductive system .


The female external urethral orifice is where urine exits the  urethra  during  urination . It is located about 2.5 cm (1 in) behind the  clitoris  and immediately in front of the  vaginal opening  in the  vulval vestibule . It usually assumes the form of a short,  sagittal  cleft with slightly raised margins. To its left and right are the openings of the  Skene's glands .


Some evidence exists to suggest that the  clitoral-urinary meatus distance  (CUMD) in human females relates to the ease with which the female may achieve  orgasm  through  penetrative sex . Orgasm from penetration alone is observed to be more likely as CUMD decreases. [ 2 ]


Evidence also suggests that decreased distance from the vaginal opening to the urethral meatus is associated with recurrent post-coital urinary tract infections. [ 3 ]  Surgical repositioning of the distal urethra to prevent recurrent post-coital urinary tract infections has been employed with some success by Russian physicians. [ 4 ]


Unlike most other mammals (including human), female  spotted hyenas  have a urinary meatus that is located on the  clitoral glans . [ 5 ] [ 6 ]


Congenital disorders  of the meatus, in the male, include  epispadias  (the misplacement to the upper aspect) and  hypospadias  (the misplacement to the underside of the penis). A congenital misshaping can result in its narrowing ( meatal stenosis ), causing a partial or total urinary blockage or the bifurcation of the urinary stream. A urethral blockage can also be caused by foreign material,  kidney stones , or  bladder stones  ( lithiasis ).


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Urinothorax  ( pl .  urinothoraces ) is defined as  urine  in the  fluid-filled cavity  that surrounds the  lungs . [ 1 ]  It is usually caused by  obstructive uropathy . It is mainly diagnosed by analyzing the  pleural fluid . Treatment involves treating the underlying condition, which typically results in resolution of the urinothorax. It is an extremely rare cause of  pleural effusion . [ 2 ]


The characteristics of people affected by urinothorax are poorly defined.  Urological symptoms  tend to occur, while the  respiratory symptoms  are typically nonexistent or mild. [ 3 ]   Difficulty breathing , occurring in moderate to large  pleural effusions , is the most common respiratory symptom. [ 4 ]  Other symptoms include  fever ,  abdominal pain ,  chest pain , and reduced  urination . [ 3 ]  It typically occurs within hours of the causative condition. [ 5 ]


Urinothorax is usually caused by  obstructive uropathy . The obstructive uropathy may be at the  urinary bladder  or  urethral  level. [ 6 ]  Obstructive causes have been caused by  prostate disease ,  kidney cyst ,  retroperitoneal fibrosis , and  supernumerary kidney . [ 3 ]  Traumatic cases tend to occur on one side, while obstructive cases tend to be bilateral. [ 2 ]  In cases caused by  urinoma , the urinothorax is usually on the same side of it. Rarely, it can be on both sides or on the opposite side of the urinoma. [ 7 ]  It can also be caused by  renal biopsy ,  kidney transplantation ,  lithotripsy , failed tube  nephrostomy , or  cancer  of the urinary tract. [ 6 ]


Injury to the  urinary tract  can result in collections of fluid known as a  urinoma . [ 4 ]  It has the smell of normal  urine . [ 5 ]  The urine arrives in the pleural space either  retroperitoneally  (under the  peritoneum ), or via the retroperitoneal  lymphatics . [ 8 ]  Urine can reach the pleural space either directly or indirectly. It can reach directly, by going through pores in the  thoracic diaphragm  due to a pressure gradient, or by a rupture of a urinoma releasing the contents into the pleural space. [ 4 ]  It can also reach indirectly, when a urinoma drains into the pleural space via linkage between the lymphatics of the retroperitoneal and pleural regions. [ 4 ]


Due to the main symptoms typically being urological rather than respiratory, the condition requires exclusion of other conditions and the identification of specific symptoms before diagnosis. [ 7 ]  Pleural fluid analysis is one way to diagnose the condition. The pleural fluid is most often straw-colored, and it has a distinct smell like  ammonia . The fluid usually has a nucleated cell count between 50 and 1500 per  cm 3 . [ 4 ]  The  pH  of the fluid is usually between 5 and 7. [ 9 ]  Primary factors for diagnosing urinothorax by pleural fluid include low protein and high  lactate dehydrogenase  content. [ 10 ]  Low  glucose  levels and  acidity  are also described, but are not reliable ways to diagnose or rule out urinothorax. [ 2 ]  The most important chemical diagnostic factor of the fluid is that the ratio of  creatinine  to  serum  is more than 1 and usually more than 10. [ 10 ]


Abdominal  ultrasonography  and  CT scan  can help diagnose the underlying condition of the  genitourinary tract . If other methods prove inconclusive, an accurate diagnosis can be made by a  technetium-99m  kidney scan, which shows albumin labeled with 99Tc that translocates into the pleural space from the genitourinary tract. [ 4 ]


Treatment mainly consists of treating the underlying disorder of the genitourinary tract. [ 2 ]  It requires a  multidisciplinary team  that includes a  pulmonologist  and  urologist . A  nephrostomy  tube or  Foley catheter  can be used to relieve any underlying obstruction. Any injuries are repaired. [ 11 ]  When the underlying disorder is addressed, the urinothorax rapidly resolves.  Thoracic surgery  is usually not needed, [ 4 ]  especially if respiratory symptoms are minimal or nonexistent. [ 2 ]   Pleurodesis  is also ineffective. [ 11 ]  A  chest tube  can be used to drain urine from the pleural cavity. [ 12 ]


Urinothoraces typically resolve spontaneously without recurring after the underlying urinary tract disorder is treated. [ 11 ]


Urinothorax remains a rare, possibly under-diagnosed, differential in the case of transudative pleural effusion. There were only 58 reported cases up until January 2006. In the literature, there are under 100 reported cases. [ 8 ]


A  UTI vaccine  is a  vaccine  used for  prevention  of recurrent  urinary tract infections  (UTIs). [ 1 ] [ 2 ]  A number of UTI vaccines have been developed and/or marketed. [ 1 ] [ 2 ] [ 3 ]  These include  Uromune  (MV-140;  sublingual   spray ),  UroVaxom  (OM-89, OM-8980;  oral   tablet ), [ 4 ]   Solco-Urovac  (Strovac;  vaginal   suppository  or  intramuscular injection ), [ 5 ] [ 6 ]   ExPEC4V  (V10, JNJ-63871860; intramuscular injection), [ 7 ]  and  SEQ-400  (route unspecified). [ 8 ]


Recurrent UTIs are common in women, causing significant physical and emotional distress. While  antibiotics  are widely used to treat them, the recurrence of UTIs poses a significant challenge. Long-term antibiotic use not only poses health risks but also contributes to the growing problem of  antibiotic resistance , making effective treatment more challenging.


Uromune  (developmental code name MV-140) is a vaccine developed to treat recurrent UTIs that is made from heat-inactivated bacteria mixed with in glycerol, sodium chloride, artificial pineapple flavoring, and water. [ 9 ]  It contains specific strains of four types of bacteria:  Escherichia coli ,  Klebsiella pneumoniae ,  Enterococcus faecalis , and  Proteus vulgaris .


This vaccine is taken by spraying it under the tongue twice a day for three months. It is currently being tested in clinical trials. Studies suggest that MV140 works by stimulating the immune system to produce antibodies and activate certain immune cells, which help protect against UTIs.


In a conducted study involving 89 individuals with a history of urinary tract infections (UTIs), participants were instructed to use two sprays of the vaccine daily for three months. Preliminary results presented at the European Association of Urology Congress in Paris revealed that nine years later, 54 percent of the participants remained free from UTIs. Women in the study remained UTI-free for approximately 4.5 years on average, while men experienced around 3.5 years without UTIs. [ 10 ]  Dr. Bob Yang, who co-led the study and serves as a consultant urologist at the  Royal Berkshire NHS Foundation Trust  in the United Kingdom, noted that before receiving the vaccine, all participants had struggled with recurrent UTIs, which can be challenging to treat.


UTI vaccines are approved for medical use in some countries or are available via special-access programs. However, UTI vaccines remain in the experimental stage of development in much of the world and remain to be approved by the  Food and Drug Administration  (FDA) in the  United States .


In  mammals , the  vulva  ( pl. :  vulvas  or  vulvae ) comprises mostly external, visible structures of the female  genitalia  leading into the interior of the female  reproductive tract . For humans, it includes the  mons pubis ,  labia majora ,  labia minora ,  clitoris ,  vestibule ,  urinary meatus ,  vaginal introitus ,  hymen , and openings of the vestibular glands ( Bartholin's  and  Skene's ). The folds of the outer and inner  labia  provide a double layer of protection for the vagina (which leads to the  uterus ).  Pelvic floor muscles  support the structures of the vulva. Other muscles of the  urogenital triangle  also give support.


Blood supply to the vulva comes from the three  pudendal arteries . The  internal pudendal veins  give drainage.  Afferent lymph vessels  carry  lymph  away from the vulva to the  inguinal lymph nodes . The nerves that supply the vulva are the  pudendal nerve ,  perineal nerve ,  ilioinguinal nerve  and their branches. Blood and nerve supply to the vulva contribute to the stages of  sexual arousal  that are helpful in the  reproduction  process.


Following the development of the vulva, changes take place at birth,  childhood ,  puberty ,  menopause  and post-menopause. There is a great deal of variation in the appearance of the vulva, particularly in relation to the labia minora. The vulva can be affected by many disorders, which may often result in  irritation .  Vulvovaginal health  measures can prevent many of these. Other disorders include a number of infections and  cancers . There are several vulval restorative surgeries known as  genitoplasties , and some of these are also used as  cosmetic surgery procedures .


Different cultures have held different views of the vulva. Some ancient religions and societies have worshipped the vulva and revered the female as a goddess. Major traditions in  Hinduism  continue this. In Western societies, there has been a largely negative attitude typified by the medical terminology of  pudenda membra , meaning parts to be ashamed of. There has been an artistic reaction to this in various attempts to bring about a more positive and natural outlook. While the  vagina  is a separate part of the anatomy, it has often been used synonymously with vulva. [ 1 ]


The human vulva is made up of the following:


The  mons pubis  is a soft mound of  fatty tissue  in the pubic region covering the  pubic bone . [ 2 ]   Mons pubis  is Latin for "pubic mound" and is present in both  sexes  to act as a cushion during  sexual intercourse , and is more pronounced in the female. [ 3 ]  The variant term  mons veneris  ('mound of Venus') is used specifically for females. [ 4 ] [ 3 ]


The  labia minora  are the small inner pair of skin folds that protect the openings. [ 5 ]  The large outer pair of folds are the  labia majora , which contain and protect the labia minora and other structures of the vulva. [ 5 ]  The labia majora meet at the front of the mons pubis, and meet posteriorly at the  urogenital triangle  (the anterior part of the  perineum ) below the  anus . [ 6 ] [ 7 ]  The labia minora are often pink or brownish black, relevant to the person's skin color. [ 8 ]


The grooves between the labia majora and minora are called the  interlabial sulci , or interlabial folds. [ 9 ]  The labia minora meet posteriorly as the frenulum ( fourchette ). [ 10 ]


Located at the anterior junction of the labia minora is the  clitoris , a highly  erogenous  sexual organ. The visible portions of the clitoris are the  glans  and  frenulum . Typically, the glans is roughly the size and shape of a  pea , and can vary in size from about 6 mm to 25 mm (less than an inch). [ 11 ]  The size can also vary when the clitoris is  erect , [ 7 ]  which happens when two regions of  erectile tissue  known as the  corpora cavernosa  (along with the  bulbs  and  crura , which both constitute the  root  of the clitoris) [ 12 ]  fill with  blood , making the  shaft  engorged. The glans contains many nerve endings, which makes it highly sensitive. [ 11 ]  The only known function of the clitoris is to focus on sexual feelings. [ 11 ]  The  clitoral hood  is a protective fold of  skin  and it may partially or completely cover the shaft and glans. [ 13 ]  The hood may be partially or completely hidden within the  pudendal cleft . [ 14 ]


The area between the labia minora where the  vaginal introitus  and the  urinary meatus  (openings of the  vagina  and  urethra  respectively) are located is the  vestibule . The meatus is below the clitoris and atop the introitus. The introitus is sometimes partly covered by a membrane called the  hymen . The hymen will usually rupture during the first episode of vigorous sex, and the blood produced by this rupture has been seen to signify  virginity . However, the hymen may also rupture spontaneously during exercise or be stretched by normal activities such as the use of  tampons  and  menstrual cups , or be so minor as to be unnoticeable, or be absent. [ 11 ]  In some rare cases, the hymen may completely cover the introitus, requiring a surgical procedure called a  hymenotomy . [ 15 ]  Two greater vestibular glands known as  Bartholin's glands  open into either side of the introitus and secrete a mucous  vaginal lubricant . [ 16 ]  The openings of the lesser vestibular glands, known as  Skene's glands , are found on either side of the urethral meatus. [ 17 ]


Pelvic floor muscles  help to support the vulvar structures. The voluntary,  pubococcygeus muscle , part of the  levator ani  muscle partially constricts the vaginal opening. [ 18 ]  Other muscles of the  urogenital triangle  support the vulvar area and they include the  transverse perineal muscles , the  bulbospongiosus , and the  ischiocavernosus  muscles. [ 19 ]  The bulbospongiosus muscle decreases the vaginal opening. [ 6 ]  They play a role in the  vaginal contractions  of  orgasm  by causing the vestibular bulbs to contract. [ 20 ]


The tissues of the vulva are highly  vascularised  and blood supply is provided by the three  pudendal arteries . [ 21 ]  Venous return is via the  external  and  internal pudendal veins . [ 22 ]
The organs and tissues of the vulva are drained by a chain of  superficial inguinal lymph nodes  located along the  blood vessels . [ 23 ]


The  ilioinguinal nerve  originates from the first lumbar nerve and gives branches that include the  anterior labial nerves , which supply the skin of the mons pubis and the labia majora. [ 24 ]  The  perineal nerve  is one of the terminal branches of the  pudendal nerve  and this branches into the  posterior labial nerves  to supply the labia. [ 24 ]  The pudendal nerve branches include the  dorsal nerve , which gives sensation to the clitoris. [ 24 ]  The clitoral glans is seen to be populated by a large number of small nerves, a number that decreases as the tissue changes towards the urethra. [ 25 ]  The density of nerves at the glans indicates that it is the center of heightened sensation. [ 25 ]   Cavernous nerves  from the  uterovaginal plexus  supply the  erectile tissue  of the clitoris. [ 26 ]  These are joined underneath the  pubic arch  by the dorsal nerve of the clitoris. [ 27 ]
The pudendal nerve enters the pelvis through the  lesser sciatic foramen  and continues medial to the internal pudendal artery. The point where the nerve circles the  ischial spine  is the location where a  pudendal block  of  local anesthetic  can be administered to inhibit sensation to the vulva. [ 28 ]  A number of smaller nerves split off from the pudendal nerve. The  deep branch of the perineal nerve  supplies the muscles of the perineum and a branch of this supplies the bulb of the vestibule. [ 29 ] [ 30 ]


There is a great deal of variation in the appearance of the vulva. [ 11 ]  Much of this variation lies in the significant differences in the size, shape, and color of the labia minora. Though called the smaller lips, they can often be of considerable size and may protrude outside the labia majora. [ 11 ] [ 7 ]  This variation has also been evidenced in a large display of 400 vulval casts called the  Great Wall of Vagina  created by  Jamie McCartney  to fill the lack of information of what a normal vulva looks like. The casts taken from a large and varied group of women showed clearly that there is much variation. [ 34 ] [ 11 ]  Other variations of the vulva include the appearance of  Fordyce spots  and clitoral phimosis (when the clitoral hood cannot retract past the glans).


Researchers from the Elizabeth Garret Anderson Hospital, London, measured multiple genital dimensions of 50 women between the ages of 18 and 50, with a mean age of 35.6: [ 35 ]


In week three of  the development of the embryo ,  mesenchyme  cells from the  primitive streak  migrate around the  cloacal membrane . [ 36 ]  Early in the fifth week, the cells form two swellings called the cloacal folds. [ 37 ]  The cloacal folds meet in front of the cloacal membrane and form a raised area known as the  genital tubercle . [ 37 ] [ 36 ]  The urorectal septum fuses with the cloacal membrane to form the  perineum . This division creates two areas one surrounded by the urethral folds and the other by the anal folds. [ 37 ] [ 36 ]  These areas become the urogenital triangle and the anal triangle. [ 38 ]  The area between the vulva and the anus is known as the clinical perineum. [ 38 ]


At the same time, a pair of swellings on either side of the urethral folds known as the genital swellings develop into the  labioscrotal swellings . [ 37 ] [ 36 ]  Sexual differentiation takes place, and at the end of week six in the female, hormones stimulate further development and the genital tubercle bends and forms the clitoris. [ 37 ] [ 36 ]  The  urogenital sinus  persists as the vulval vestibule, vestibular glands and urethra. The  urethral folds  form the labia minora and the labioscrotal swellings form the labia majora. [ 39 ] [ 40 ]


The uterovaginal canal or genital canal, forms in the third month of the development of the urogenital system. The lower part of the canal is blocked off by a plate of tissue, the vaginal plate. This tissue develops and lengthens during the third to fifth months and the lower part of the vaginal canal is formed by a process of desquamation or cell shedding. The end of the vaginal canal is blocked off by an endodermal membrane, which separates the opening from the vestibule. In the fifth month, the membrane degenerates but leaves a remnant called the hymen. [ 37 ]


The  newborn 's vulva may be swollen or enlarged as a result of having been exposed, via the  placenta , to her mother's increased levels of hormones. [ 41 ]  The labia majora are closed. [ 42 ]  These changes disappear over the first few months. [ 41 ]  During childhood before puberty, the lack of estrogen can cause the labia to become sticky and to ultimately join firmly together. This condition is known as  labial fusion  and is rarely found after puberty when estrogen production has increased. [ 43 ]


Puberty  is the onset of the ability to reproduce, and takes place over two to three years, producing a number of changes. [ 44 ] [ 45 ]  The structures of the vulva become proportionately larger and may become more pronounced. [ 46 ]   Pubarche , the first appearance of  pubic hair  develops, firstly on the labia majora, and later spreads to the mons pubis, and sometimes to the inner thighs and perineum. Pubic hair is much coarser than other body hair, and is considered a  secondary sex characteristic . [ 47 ]  Pubarche can occur independently of puberty.  Premature pubarche  may sometimes indicate a later  metabolic - endocrine disorder  seen at adolescence. The disorder sometimes known as a  polyendocrine disorder  is marked by elevated levels of  androgen ,  insulin , and  lipids , and may originate in the fetus. Instead of being seen as a normal variant it is proposed that premature pubarche may be seen as a marker for these later endocrine disorders. [ 48 ]


Apocrine sweat glands  secrete  sweat  into the pubic hair follicles. This is broken down by bacteria on the skin and produces an odor, [ 49 ]  which some consider to act as an attractant  sex pheromone . [ 50 ]  The labia minora may grow more prominent and undergo changes in color. [ 35 ]  At puberty, the first monthly period known as  menarche  marks the onset of  menstruation . [ 51 ]
In prepubertal girls, the skin of the vulva is thin and delicate, and its neutral pH makes it prone to irritation. [ 52 ]  The production of the female sex hormone  estradiol  (an  estrogen ) at puberty, causes the perineal skin to thicken by  keratinising , and this reduces the risk of infection. [ 53 ]  Estrogen also causes the laying down of fat in the development of the secondary sex characteristics. This contributes to the maturation of the vulva with increases in the size of the mons pubis, and the labia majora and the enlargement of the labia minora. [ 46 ]


In  pregnancy , the vulva and vagina take on a bluish coloring due to venous congestion. This appears between the eighth and twelfth week and continues to darken as the pregnancy continues. [ 38 ]  Estrogen is produced in large quantities during pregnancy and this causes the vulva to become enlarged. The vaginal opening and the vagina are also enlarged. [ 54 ]  After  childbirth , a vaginal discharge known as  lochia  is produced and continues for about ten days. [ 54 ]


During  menopause , hormone levels decrease, which causes changes in the vulva known as  vulvovaginal atrophy . [ 55 ]  The decreased estrogen affects the mons, the labia, and the vaginal opening and can cause pale, itchy, and sore skin. [ 55 ]  Other visible changes are a thinning of the pubic hair, a loss of fat from the labia majora, a thinning of the labia minora, and a narrowing of the vaginal opening. This condition has been renamed by some bodies as the  genitourinary syndrome of menopause  as a more comprehensive term. [ 55 ]


The vulva has a major role to play in the reproductive system. It provides entry to, and protection for the uterus, and the right conditions in terms of warmth and moisture that aids in its sexual and reproductive functions. The vulva is richly innervated and provides pleasure when properly stimulated. The mons pubis provides cushioning against the pubic bone during intercourse. [ 11 ]


A number of different secretions are associated with the vulva, including  urine  (from the urethral opening during  urination  through control of the  external sphincter muscle ),  sweat  (from the apocrine glands),  menses  (leaving from the vagina via the introitus),  sebum  (from the  sebaceous glands ), alkaline fluid (from the Bartholin's glands),  mucus  (from the Skene's glands), vaginal lubrication from the  vaginal wall  and  smegma . [ 38 ] [ 11 ]  Smegma is a white substance formed from a combination of dead cells, skin oils, moisture and naturally occurring  bacteria , that forms in the genitalia. [ 56 ]  In females, this thickened secretion collects around the clitoris and labial folds. It can cause discomfort during  sexual activity  as it can cause the clitoral glans to stick to the hood, and is easily removed by bathing. [ 11 ]   Aliphatic  acids known as  copulins  are also secreted in the vagina. [ 50 ]  These are believed to act as  pheromones . Their  fatty acid  composition, and consequently their  odor  changes in relation to the stages of the  menstrual cycle . [ 50 ]


The clitoris and the labia minora are both the most  erogenous areas  of the vulva. The labia majora are also somewhat erogenous. [ 57 ]  Local  stimulation  can involve the clitoris, vagina and other perineal regions. The clitoris (especially the glans) is the human female's most sensitive erogenous zone and generally the primary anatomical source of human female sexual pleasure. [ 58 ]  Sexual stimulation of the clitoris (by a number of means) can result in widespread sexual arousal and, if maintained, can result in  orgasm . Stimulation to vulvar orgasm is optimally achieved by a massaging sensation, [ 46 ]  such as  oral sex  ( cunnilingus ),  fingering , and  tribadism  (two women rubbing vulvas together).


Sexual arousal results in a number of physical changes in the vulva. During arousal, the  Bartholin's glands  produce more  vaginal lubrication . Vulval tissue is highly  vascularised ; arterioles dilate in response to sexual arousal and the smaller veins will compress after arousal, [ 29 ] [ 59 ]  so that the clitoris and labia minora increase in size. Increased  vasocongestion  in the vagina causes it to swell, decreasing the size of the vaginal opening by about 30%.  Clitoral erection  takes place, which retracts the clitoral hood, causing the glans to appear. The labia majora have swollen from blood flow, [ 60 ]  and slightly separated, revealing a thick and engorged labia minora. [ 61 ]  The labia minora sometimes change considerably in color, going from pink to red in lighter skinned women who have not borne a child, or red to dark red in those who have.


During orgasm, rhythmic  muscle contractions  occur in the outer third of the vagina, as well as the uterus and anus. Contractions become less intense and more randomly spaced as the orgasm continues. The number of contractions that accompany an orgasm vary depending on its intensity. An orgasm may be accompanied by  female ejaculation , causing liquid from the  Skene's glands  to be expelled through the urethra. The pooled blood begins to dissipate, although at a much slower rate if an orgasm has not occurred. The vagina and its opening return to their normal relaxed state, and the rest of the vulva returns to its normal size, position and color. [ 62 ] [ 11 ]


Irritation and  itching  of the vulva is called  pruritus vulvae . This can be a symptom of many disorders, some of which may be determined by a  patch test . The most common cause of irritation is  thrush , a fungal infection.  Vulvovaginal health  measures can help to prevent many disorders including thrush. [ 63 ]  Infections of the vagina such as  vaginosis  and of the uterus may produce  vaginal discharge , which can be an  irritant  when it comes into contact with the vulvar tissue. [ 64 ] [ 65 ]  Inflammation as  vaginitis ,  vulvovaginitis  and  vulvitis  can result from this causing irritation and pain. [ 66 ]   Ingrown hairs  resulting from pubic hair shaving can cause  folliculitis  where the  hair follicle  becomes infected; or give rise to an inflammatory response known as  pseudofolliculitis pubis . [ 67 ]  A less common cause of irritation is  genital lichen planus , another inflammatory disorder. A severe variant of this is  vulvovaginal-gingival syndrome , which can lead to narrowing of the vagina, [ 68 ]  or vulva destruction. [ 69 ]  Many types of infection and other diseases including some  cancers  may cause irritation. [ 70 ] [ 71 ]


Vulvar organs and tissues can become affected by different  infectious agents  such as  bacteria  and  viruses , or  infested  by  parasites  such as  lice  and  mites . Over thirty types of  pathogen  can be  sexually transmitted , and many of these affect the genitals. Most  STIs  do not produce symptoms or symptoms may be mild and not be indicative of an STI. [ 72 ]  The practice of  safe sex  can greatly reduce the risk of infection from many sexually transmitted pathogens. [ 73 ]  The use of  condoms  (either male or  female condoms ) is one of the most effective methods of protection. [ 72 ]


Bacterial  infections include:  chancroid  – characterised by  genital ulcers  known as  chancres ;  granuloma inguinale  showing as inflammatory  granulomas  often described as nodules;  syphilis  –the primary stage classically presents with a single chancre, a firm, painless, non-itchy ulcer, but there may be multiple sores; [ 74 ]  and  gonorrhea  that very often presents no symptoms but can result in discharge. [ 75 ]


Viral infections  include  human papillomavirus infection  (HPV) – this is the most common  STI  and has many types. [ 76 ]  Genital HPV can cause  genital warts . There have been links made between HPV and vulvar cancer, though HPV most often causes  cervical cancer . [ 77 ]   Genital herpes  is mostly  asymptomatic  but can present with small  blisters  that break open into  ulcers . [ 78 ]   HIV/AIDS  is mostly transmitted through sexual activity, and the vulva in some cases can be affected by sores. [ 79 ]
A highly contagious viral infection is  molluscum contagiosum , which is transmissible on close contact and causes water  warts . [ 80 ] [ 81 ]


Parasitic  infections include  trichomoniasis ,  pediculosis pubis , and  scabies . Trichomoniasis is transmitted by a  parasitic   protozoan  and is the most common non-viral STI. [ 82 ]  Most cases are asymptomatic but may present symptoms of irritation and a  discharge  of unusual  odor . [ 83 ]   Pediculosis pubis , commonly called  crabs , is a disease caused by the  crab louse  an  ectoparasite . [ 71 ]  When the pubic hair is infested, the irritation produced can be intense. [ 71 ]   Scabies , also known as the "seven year itch", is caused by another ectoparasite, the  mite   Sarcoptes scabiei , giving intense irritation. [ 71 ]


Malignancies  can develop in the glabrous and hair-bearing parts of the vulva. [ 29 ] [ 84 ]  Based on the cellular origin and  histology , vulvar cancers are classified into  squamous cell carcinomas ,  melanomas ,  basal cell carcinomas ,  adenocarcinomas ,  sarcomas  and invasive  extramammary Paget's disease . [ 84 ]  Squamous cell carcinomas represent the most common variant of vulvar cancers and account for approximately 75%. [ 84 ]  These are usually found in the labia, particularly the labia majora. [ 85 ]  The second most common vulvar cancer is  basal cell carcinoma , which rarely spreads to regional lymph nodes or distant organs. [ 84 ]  The third most common subtype is vulvar  melanoma . Studies have shown that vulvar melanomas appear to have a different tumor biology and mutational characteristics compared to skin  melanomas , which has a direct impact on the medical treatment of vulvar melanomas. [ 86 ] [ 87 ]


Signs  and symptoms of vulvar cancer can include:  itching , or  bleeding ; skin changes including rashes, sores, lumps or  ulcers , and changes in vulvar skin coloration.  Pelvic pain  might also occur especially during  urinating  and sex. [ 70 ]  However, a significant proportion remains asymptomatic in early disease stages, often delaying its diagnosis. [ 84 ]  As such, 32% of women with vulvar melanoma already have regional involvement or distant metastases at the time of diagnosis, which significantly impacts prognosis. [ 86 ]


Surgery (with or without removal of regional lymph nodes) is usually the primary treatment modality. Typically, a wide-local excision is performed, in which the tumor is excised including a safety-margin of healthy tissue to ensure its entire removal, which is confirmed by a pathologist. [ 84 ]  In more advanced disease, a (partial)  vulvectomy  may need to be performed in order to remove some or all of the vulva. [ 88 ]  Advanced-stage melanomas can be treated with  checkpoint inhibitors . [ 89 ]


Labial fusion , also called  labial adhesion , is the fusion of the labia minora. This affects a number of young girls and is not considered unduly problematic. The condition can usually be treated using  creams , or it may right itself with the release of hormones at the onset of puberty. [ 43 ] [ 90 ]


Clitoromegaly  is an enlarged clitoris caused by either  anabolic steroids   or an  intersex  condition.


Vulvodynia  is chronic pain in the vulvar region. There is no single identifiable cause. [ 91 ]  A subtype of this is  vulvar vestibulitis  but since this is not thought to be an inflammatory condition it is more usually referred to as  vestibulodynia . [ 92 ]  Vulvar vestibulitis usually affects pre-menopausal women. [ 92 ]


Pudendal nerve entrapment  can cause sharp pain or numbness in the vulva. This condition can be caused by activities such as  cycling , giving birth, or prolonged sitting.


A number of  skin disorders  such as  lichen sclerosus , and  lichen simplex chronicus  can affect the vulva.  Crohn's disease  of the vulva is an uncommon form of  metastatic  Crohn's disease, which manifests as a skin condition showing as  hypertrophic  lesions or vulvar  abscesses . [ 93 ]   Papillary hidradenomas  are  nodules  that can ulcerate and are mostly found on the skin of the labia or of the interlabial folds. Another more complex ulcerative condition is  hidradenitis suppurativa , which is characterised by painful cysts that can ulcerate, and recur, and can become chronic lasting for many years. [ 94 ] [ 95 ]  Chronic cases can develop into  squamous cell carcinomas . [ 95 ]  An asymptomatic skin disorder of the vulval vestibule is  vestibular papillomatosis , which is characterised by fine, pink projections from either the epithelium of the vulva or from the labia minora.  Dermatoscopy  can distinguish this condition from genital warts. [ 96 ]  A subtype of  psoriasis , an  autoimmune disease , is  inverse psoriasis  in which red patches can appear in the  skin folds  of the labia. [ 97 ]


The vulvar region is at risk for trauma during  childbirth . [ 98 ]
During childbirth, the vagina and vulva must stretch to accommodate the baby's head (approximately 9.5 cm (3.7 in)). This can result in tears known as  perineal tears  in the vaginal opening, and other structures within the  perineum . [ 99 ]  An  episiotomy  (a pre-emptive surgical cutting of the perineum) is sometimes performed to facilitate delivery and limit tearing. A tear takes longer to heal than an incision. [ 100 ]  Tears and incisions may be repaired using  sutures  that may be layered. [ 101 ] [ 38 ]  Among the methods of hair removal evaluated for pre-surgeries, pubic hair shaving known as  prepping , was seen to increase the risk of surgical site infections. [ 102 ] [ 100 ]  No advantages have been demonstrated in the routine shaving of pubic hair prior to childbirth. [ 103 ]


Genitoplasties  are  plastic surgeries  that can be carried out to repair, restore or alter vulvar tissues, [ 104 ]  particularly following damage caused by injury or  cancer treatment . These procedures include  vaginoplasty  and  vulvoplasty , which can also be performed as a  cosmetic surgery . Other cosmetic surgeries to change the appearance of external structures include  labiaplasties . [ 105 ]  Some of these procedures, vaginoplasties and vulvoplasties, are also carried out as  sex reassignment surgeries . [ 106 ] [ 107 ]


The use of cosmetic surgeries has been criticized by clinicians. [ 108 ] [ 109 ]  The  American College of Obstetricians and Gynecologists  recommends that women be informed of the risks of these surgeries. They refer to the lack of data relevant to their safety and effectiveness and to the potential associated risks such as  infection , altered sensation,  dyspareunia ,  adhesions , and  scarring . [ 110 ]  There is also a percentage of people seeking cosmetic surgery who may be suffering from  body dysmorphic disorder  and surgery in these cases can be counterproductive. [ 111 ]


In some  cultural practices , particularly in the African  Khoikhoi  and  Rwanda  cultures, the labia minora are purposefully stretched by repeated pulling on them and sometimes by attaching weights. [ 112 ] [ 113 ] [ 11 ]   Labia stretching  is a recognised, familial cultural practice in parts of Eastern and Southern Africa. [ 112 ] [ 114 ] [ 115 ]  This is a desired and encouraged practice by the women (starting at puberty) in order to promote better sexual satisfaction for both parties. [ 116 ] [ 11 ]  The achieved extensions can hang down below the labia majora for up to seven inches. [ 11 ]  Children in the African diaspora practise this too, so it occurs within immigrant communities in, for example, Britain, where a  BBC News  report labelled it a hidden form of  child abuse . [ 117 ]  The girls are subject to familial and social pressure to conform. [ 118 ]


In some cultures, including modern Western culture, women have shaved or otherwise  removed the hair  from part or all of the vulva. When high-cut swimsuits became fashionable, women who wished to wear them would remove the hair on either side of their pubic triangles, to avoid exhibiting  pubic hair . [ 119 ]  Other women prefer to retain their vulva hair. The removal of hair from the vulva is a fairly recent phenomenon in the United States, Canada, and Western Europe, usually in the form of  bikini waxing  or  Brazilian waxing , but has been prevalent in many Eastern European and Middle Eastern cultures for centuries, usually due to the idea that it may be more hygienic, or originating in prostitution and pornography. [ 120 ] [ 121 ]  Hair removal may include all, most, or some of the hair. [ 122 ]   French waxing  leaves a small amount of hair on either side of the labia or a strip directly above and in line with the pudendal cleft called a  landing strip . [ 122 ]   Islam  teaching includes  Muslim hygienical jurisprudence  a  practice  of which is the removal of pubic hair. [ 123 ]


Several forms of  genital piercings  can be made in the vulva, and include the  Christina ,  Princess Albertina ,  Isabella ,  Nefertiti ,  fourchette , and  labia piercings . Piercings are usually performed for aesthetic purposes, but some forms like the  clitoral hood piercing  (or rarely  glans piercing ) might also enhance pleasure during sex. Though they are common in  traditional cultures , intimate piercings are a fairly recent trend in Western society. [ 124 ] [ 125 ] [ 126 ]  Other forms of permanent modifications of the vulva for cultural, decorative or aesthetic reasons are  genital tattoos  or  scarification  (so-called "Hanabira").


Female genital surgery includes  laser resurfacing  of the labia to remove wrinkles,  labiaplasty  (reducing the size of the labia) and  vaginoplasty . In September 2007, the  American College of Obstetricians and Gynecologists  (ACOG) issued a committee opinion on these and other female genital surgeries, including "vaginal rejuvenation", "designer vaginoplasty", "revirgination", and " G-spot  amplification". This opinion states that the safety of these procedures has not been documented. The ACOG and the  ISSVD  recommend that women seeking these surgeries need to be informed about the lack of data supporting these procedures and the potential associated risks such as infection, altered sensation,  dyspareunia ,  adhesions , and scarring. [ 110 ] [ 127 ]


With the growing popularity of female cosmetic genital surgeries, the practice increasingly draws criticism from an opposition movement of  cyberfeminist  activist groups and platforms, called the  labia pride movement . The major point of contention is that heavy advertising for these procedures, in combination with a lack of public education, fosters body insecurities in women with larger labia in spite of the fact that there is normal and pronounced individual variation in the size of labia. The preference for smaller labia is a matter of a fashion fad and is without clinical or functional significance. [ 128 ] [ 129 ]


The most prevalent form of non-consensual  genital alteration  is that of  female genital mutilation . This mostly involves the partial or complete removal of the vulva. [ 130 ]  Female genital mutilation is carried out in thirty countries in Africa and Asia with more than 200 million girls being affected, and some women (as of 2018). [ 130 ]  Nearly all of the procedures are carried out on young girls. The practices are also carried out globally among migrants from these areas. Female genital mutilation is claimed to be mostly carried out for cultural traditional reasons. [ 130 ]  According to the research conducted under  In the Name of Tradition , FGM/C is more common in  Sunni  countries and less common in  Shia  societies. [ 131 ] [ 132 ] [ 133 ] [ 134 ]


FGM/C can have harmful effects on their physical and mental health. Various official and unofficial research reports also confirm these complications. In its various reports, the  World Health Organization  has considered FGM/C as an action that endangers women's health in various ways. This organization stated in a report published in January 2023 that FGM/C has no health benefits, and it harms girls and women in many ways. It involves removing and damaging healthy and normal female genital tissue, and it interferes with the natural functions of girls' and women's bodies. Although all forms of FGM/C are associated with increased risk of health complications, the risk is greater with more severe forms of FGM/C. [ 135 ] [ 136 ] [ 137 ]


The American National Library of Medicine also stated in an article in 2018 that the consequences of FGM/C have both physiological and psychological complications, including short- and long-term complications. The method in which the procedure is performed may determine the extent of the short-term complications. If the process was completed using unsterile equipment, no antiseptics, and no antibiotics, the victim may have increased risk of complications. Primary infections include staphylococcus infections, urinary tract infections, excessive and uncontrollable pain, and hemorrhaging. Infections such as human immunodeficiency virus ( HIV ), Chlamydia  trachomatis , Clostridium tetani, and herpes simplex virus (HSV) 2 are significantly more common among women who underwent Type 3 mutilation compared with other categories. [ 138 ] [ 139 ] [ 140 ]


The word  vulva  is  Latin  for "womb". It derives from the 1540s in referring to the womb and female sexual organs, from the earlier  volvere  meaning to turn, roll or revolve, with further derivatives such as used in  volvox , and  volvulus  (twisted bowel). [ 141 ] [ 142 ]  The naming of the female (and male) genitals as  pudenda membra , meaning parts to be ashamed of, dates from the mid-17th century. [ 143 ]  The naming influenced the general perception of the vulva and this is shown in depicted  gynaecological  procedures. The examiner shown in the  Obstetrical examination  dated 1822, is adopting the compromise procedure where the woman's genitals cannot be seen. [ 144 ] [ 145 ]


In 2021, a study in the UK showed that few are able to label the structure of the vulva correctly. [ 146 ] [ 147 ] [ 148 ]  There are many  sexual slang  terms used for the vulva. [ 142 ] [ 149 ]  " Cunt ", a medieval word for the vulva and once the standard term, has become a  vulgarism , and in other uses one of the strongest offensive and abusive  swear words  in English-speaking cultures. The word has been replaced in normal usage by a few  euphemisms  including " pussy " (vulgar slang) and " fanny " (UK), which used to be a common  pet name . [ 150 ] [ 142 ]  In the UK, these terms have other non-sexual meanings that lend themselves to  double entendres , such as "pussy", which is used as a  term of endearment  for a pet cat, "pussy cat". [ 151 ] [ 152 ] [ 153 ]  In North American informal use, the term "pussy" can also refer to a weak or effeminate man, [ 154 ]  and "fanny" is a term used for the  buttocks . [ 155 ] [ 142 ]  Other slang terms are "muff", "snatch", and " twat ". [ 156 ] [ 157 ]  "Vagina" is often incorrectly used as a synonym for vulva since it is separate from that anatomy. [ 1 ]


Some cultures have long celebrated and even worshipped the vulva. During the  Uruk period  ( c.  4000–3100 BC), the ancient  Sumerians  regarded the vulva as sacred [ 158 ] [ 159 ]  and a vast number of  Sumerian poems  praising the vulva of  Inanna , the goddess of love, sex, and fertility, have survived. [ 159 ]  In  Sumerian religion , the goddess  Ninimma  is the divine personification of the vulva. [ 160 ] [ 161 ]  Vaginal fluid is always described in Sumerian texts as tasting "sweet" [ 159 ]  and, in a Sumerian bridal hymn, a young maiden rejoices that her vulva has grown hair. [ 159 ]  Clay models of vulvas were discovered in the temple of Inanna at  Ashur . [ 162 ]


Some major  Hindu  traditions such as  Shaktism , a goddess-centered tradition, revere the vulva and vagina under the name  yoni . [ 163 ] [ 164 ]  The  goddess  as  Devi  is worshipped as the supreme deity. [ 165 ]  The yoni is a representation of the female deity and is found in many temples as a focus for  prayer and offerings . [ 164 ]  It is also represented symbolically as a  mudra  in  spiritual practices , including  yoga . [ 166 ]


Sheela na gigs  are figurative carvings of naked women displaying an exaggerated vulva. They are found in ancient and medieval European contexts. They are displayed on many churches, but their origin and significance is debatable. A main line of thinking is that they were used to ward off  evil spirits . Another view is that the sheela na gig was a divine assistant in childbirth. [ 167 ] [ 168 ]  Starr Goode explores the image and possible meanings of the Sheela na gig and  Baubo  images in particular, but writes also about the recurring image worldwide. Through hundreds of photographs, she demonstrates that the image of a female displaying her vulva is not specific to European religious art or architecture, but that similar images are found in the visual arts and in mythical narratives of  goddesses  and  heroines  parting their thighs to reveal what she calls, "sacred powers". Her theory is that "the image is so rooted in our psyches that it seems as if the icon is the original cosmological center of the human imagination". [ 169 ]


L'Origine du monde  ( Origin of the World ), painted by  Gustave Courbet  in 1866, was an early  Realist  painting of a vulva that only became exhibited many years later. [ 170 ]  The painting was commissioned by  Ottoman  diplomat  Halil Şerif Paşa . The woman used as the model for the painting was probably Halil's lover  Constance Quéniaux . [ 171 ]  However, another potential model is  Marie-Anne Detourbay , who was also a lover of Halil Şerif Pasha. [ 172 ]


Japanese sculptor and  manga  artist  Megumi Igarashi  has focused much of her work on painting and modelling vulvas and vulva-themed works. She has used molds to create  dioramas  – three-dimensional models of her vulva with the hope of demystifying the female genitals. [ 173 ]


An  art installation  called  The Dinner Party  by  feminist artist ,  Judy Chicago , portrays a symbolic history of famous women. The dinner plates each depict an elaborate vulval form and they are arranged in a triangular vulva shape. [ 174 ]  Another installation was made by British artist  Jamie McCartney  who used the casts of four hundred vulvas to create  The Great Wall of Vagina  in 2011. The casts are life-size. Explanations written by the project's sexual health adviser accompany these. The purpose of the artist was to "address some of the stigmas and misconceptions that are commonplace". [ 175 ] [ 34 ]


As a rule, only the external female genitals of  placental mammals  are referred to as the "vulva", although the term is also used in the scientific literature for functionally comparable structures in other animal groups such as  marsupials [ 176 ]  and roundworms ( Nematoda ). [ 177 ]


For comparison,  birds ,  reptiles ,  amphibians , and  monotremes  have a  cloaca . An organ system like a vulva does not exist.


The vulva of a placental consists of the following along with its variations:


During  estrus , the clitoris of a  mare  (female horse) everts as the labia contracts by opening and closing. This is colloquially known as "winking". [ 187 ]  Throughout the menstrual cycle, some female  primates ' vulvar and anal regions will swell ( sexual swelling ) to attract a male, though the fundamental reason for this function is up for debate. [ 188 ]


The vulva of a  spotted hyena  has a large clitoris known as a  pseudo-penis  for copulating, giving birth and urinating, as well as fused labia (pseudo- scrotum ). This can make it difficult to correctly  sex  the species.


Frasier syndrome  is a  urogenital  anomaly associated with the  WT1  (Wilms tumor 1 gene) gene. [ 1 ] [ 2 ] [ 3 ]


It was first characterized in 1964. [ 4 ]


Both males and females can have Frasier syndrome but their presentations can be different. Affected females usually have normal genitalia and gonads and have only the features of impaired renal function, which may not present until early childhood or even adolescence. Because females do not have all the features of the condition (e.g. gonadal dysgenesis), females are usually given the diagnosis of isolated nephrotic syndrome  Medline ref . Frasier syndrome in some infants may therefore go unrecognized until the affected child presents with signs of renal impairment and further testing is undertaken to evaluate the cause. In infants with XY genotype it causes an intersex condition as a result of gonadal dysgenesis. Although males with Frasier syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia may not look clearly male or clearly female (ambiguous genitalia) or the genitalia appear completely female. The internal reproductive organs (gonads) are typically undeveloped and referred to as streak gonads.  Source  These abnormal gonads are nonfunctional and often become cancerous, so they are usually removed surgically early in life. Renal features of the condition include progressive glomerulonephropathy (focal segmental  glomerulosclerosis ). Patients are also at increased risk of genito-urinary tumors (usually  gonadoblastoma ). [ citation needed ]


The glomerulonephropathy presents later than in  Denys-Drash syndrome , and the tumour risk  phenotype  is different; whilst Denys–Drash syndrome is associated with  Wilms' tumour , Frasier syndrome is associated with  gonadoblastoma . Differentiating between the two syndromes can be challenging. [ 5 ]


The  WT1  gene exists on  chromosome 11  (at 11p13), and codes for a four  zinc finger   transcription factor . Its role as a transcription factor is related to proper kidney and gonadal development. [ 6 ] [ 7 ]  The link between kidney and gonadal development and  WT1  was highlighted in past studies looking at the related Denys–Drash syndrome. Results of various investigations identified the loss of function of  WT1  to be a prerequisite of Wilms' tumour development, and also a key trait of individuals with genital abnormalities. [ 8 ]


Mutations responsible for Frasier syndrome predominantly occur in  intron  9 of the  WT1  gene, specifically  nucleotide substitutions  that influence an  intron splice site . Mutations in this region proved for the absence of three amino acids— K   T   S —between the third and fourth  WT1  zinc fingers. [ 9 ]  Referring to the autosomal dominant expressive nature of this disease, it is only necessary for an individual to have one complement of the mutated intronic sequence to appear affected. [ 10 ]  Differing from the similar Denys-Drash syndrome, where a mutated form of the WT1 protein exists, Frasier syndrome expression works solely on the existence of a changed ratio of KTS  isoforms : normal WT1 proteins including the KTS site (+KTS), and mutated, shortened proteins lacking the KTS site (−KTS). [ 1 ]  Through  alternative splicing , a specific ratio of the two isoforms normally exists, though the mutation in the intron 9 splice site severely lowers levels of the +KTS isoform; this leads to Frasier syndrome. [ 9 ]


Frasier syndrome is inherited in an  autosomal dominant  fashion, indicating the need for only one mutated allele in a cell to lead to expression of the disease. Mutations predominantly occur  de novo , allowing for expression in an individual that has no family history of it. The mutations occur during gamete formation or early in  embryogenesis . [ 10 ]


Genetic screening of children experiencing  amenorrhea  and steroid resistant nephrotic syndrome can diagnose Fraiser syndrome early, although the slow progression of renal failure makes diagnosis difficult.  [ 11 ]


Reconstructive surgery is an option for this condition  [ citation needed ]


A  reproductive system disease  is any  disease  of the  human reproductive system .


Reproductive tract infection  ( RTI ) are  infections  that affect the reproductive tract, which is part of the  reproductive system . For females, reproductive tract infections can affect the upper reproductive tract ( fallopian tubes ,  ovary  and  uterus ) and the lower reproductive tract ( vagina ,  cervix  and  vulva ); for males these infections affect the  penis ,  testicles ,  urethra  or the  vas deferens . The three types of reproductive tract infections are  endogenous infections ,  iatrogenic infections  and the more commonly known  sexually transmitted infections . [ 1 ]  Each has its own specific causes and  symptoms , caused by a bacterium, virus, fungus or other organism. Some infections are easily treatable and can be cured, some are more difficult, and some are non curable such as  AIDS  and  herpes . [ 2 ]


Examples of  congenital abnormalities  of the reproductive system include: [ citation needed ]


Examples of  cancers  of the reproductive system include: [ citation needed ]


Examples of  functional problems  of the reproductive system include:


It is also known that  disruption of the endocrine system  by certain chemicals adversely affects the development of the reproductive system and can cause vaginal  cancer . [ 4 ]  Many other reproductive diseases have also been link to exposure to synthetic and environmental chemicals. Common chemicals with known links to reproductive disorders include:  lead ,  dioxins and dioxin-like compounds ,  styrene ,  toluene , BPA ( Bisphenol A ) and  pesticides . [ 5 ]


Testicular atrophy  is a medical condition in which one or both  testicles  (or "testes") diminish in size and may be accompanied by reduced testicular function. Testicular atrophy is not related to the temporary shrinkage of the surrounding  scrotum , which might occur in response to cold temperature.


As the testicles are involved in testosterone and sperm production, the signs and symptoms of testicular atrophy overlap with those related to infertility or low testosterone levels. [ 1 ]  In a prepubescent person with testicular atrophy, there may be underdevelopment of secondary sex characteristics (e.g. lack of penis growth). [ 2 ]  In sexually developed individuals, testicular atrophy may be accompanied with lower sex drive and increased breast tissue. [ 1 ]  Additional signs and symptoms vary and can depend on the specific cause of the testicle shrinkage. Some causes include age, [ 1 ]  alcohol use, [ 3 ]  anabolic steroid use, [ 4 ]  testosterone replacement therapy, [ 2 ] [ 5 ]  direct damage to the testicles, [ 6 ] [ 7 ]  and infection. [ 8 ] [ 9 ]


Diagnosis of testicular atrophy includes physical examination of the testicles as well as imaging to measure testicular volume. [ 7 ] [ 10 ]  A testosterone blood level is also taken to assess function of the testicles. [ 1 ]  Additional tests may be ordered depending on the suspected cause(s) of the shrinkage. Treatment and potential reversibility of testicular atrophy are also dependent on the cause. [ medical citation needed ]


There are different signs and symptoms associated with testicular atrophy depending on the person's age. Symptoms before puberty are centered more around the stunting of sexual characteristics associated with hormonal changes, while symptoms after puberty include a wider range of factors. Other signs and symptoms may stem from underlying conditions which cause testicular atrophy. The most perceptible sign of testicular atrophy is shrinkage of the testicle(s). [ 11 ]


Signs and symptoms before puberty include:


Testosterone is a hormone that is found primarily in a portion of the male reproductive system called the testes and is normally measured in nanograms per deciliter. Testosterone is in charge of the growth and production of many sexual attributes in males, including facial hair, pubic hair, penis size, vocal and muscle mass changes, regulation of sex drive, and sperm production. Normal testosterone levels in males who have not yet hit puberty are less than 20 nanograms per deciliter. Low testosterone can be defined as  hypogonadism  in people with testes. Hypogonadism in people with testes is established as the hormonal inhibition of testosterone that can either be inherited or acquired at a later stage in life. Under the circumstances of pre-pubescent hypogonadism, many sexual developmental characteristics may be altered. Testosterone affects hair growth by regulating the follicle itself, which in turn affects the specific growth phases of the hair follicle. As a person with testes hits puberty, androgen, a steroid sex hormone, is produced at an increased rate, which creates terminal hair follicles. Terminal hair follicles create thicker and more pigmented hair which is also regulated by testosterone production. Testosterone also impacts pre-pubescent penis size by providing penile tissue with girth and density. The drop in testosterone values is mainly due to significant impairment of Leydig cells brought upon by hypogonadism. Leydig cells are located in the testes and serve to create testosterone and androgen. Once they are damaged, the production of testosterone is stunted. [ 13 ]


Signs and symptoms after puberty include: [ medical citation needed ]


Typical testosterone levels of people with testes after puberty range from 300 to 1,200 nanograms per deciliter. Low testosterone values in males post-puberty would be considered any value under 300 nanograms per deciliter. Decreased testosterone values caused by testicular atrophy can lead to and explain many of the signs and symptoms listed above, including a reduced sex drive, infertility, soft testicles, reduction of hair, and lower muscle mass throughout the body. Testosterone plays an important role in physiologically stimulating sex drive in people with testes. If testosterone levels drop below normal values, libido (sexual drive) is reduced, which can lead to the development of erectile dysfunction (a condition in which the penis is not able to get or stay erect). [ 14 ]  This can indirectly affect fertility as well. In addition, testosterone is important in muscle mass formation. It increases the amount of lean muscle mass in the body. Testosterone encourages metabolic activity in the body, which in turn stimulates protein synthesis.  Protein synthesis  is highly important for the development and enlargement of muscle. Therefore, a lack of testosterone would alter this metabolic process, leading to a decrease in muscle mass. [ 15 ]


Signs and symptoms of testicular atrophy that are due to a secondary medical condition include:


Secondary medical conditions that may cause the signs and symptoms listed above include testicular cancer, chronic alcohol use, sexually transmitted infections, COVID-19, orchitis, varicoceles, or torsion of the testes. [ 8 ] [ 11 ]


Shrinkage of the testicles is common with advanced age, as overall reproductive function declines. [ 1 ] [ 2 ]


High alcohol usage lowers testosterone levels by direct damage to the  Leydig cells  (which produce testosterone) and by affecting hormones involved in signaling to the Leydig cells to produce testosterone. [ 3 ]  As a result, testicular atrophy is a common feature among individuals with high alcohol use. [ 3 ]  Testicular malformations and low testosterone levels is also commonly found in people with  alcoholic cirrhosis  as the negative effect of alcohol use is worsened by the liver damage itself. [ 3 ]  Excessive alcohol intake can cause inflammation and the degradation of cells in the liver, which can then cause testicular abnormalities (including testicular atrophy). [ 16 ]


Anabolic steroid  use and  testosterone replacement therapy (TRT)  have been found to cause testicular atrophy through similar mechanisms. [ 2 ] [ 1 ] [ 17 ]  Anabolic steroids and TRT are both used (either by prescription or illicitly) to mimic the effects of testosterone produced by the body, such as building muscle and maintaining sex drive. [ 17 ] [ 1 ] [ 2 ]  However, they also inhibit the body's own production of sperm and testosterone, which can lead to shrinkage of the testicles. [ 17 ] [ 4 ]


Testicular atrophy is also a side effect of estrogen therapy. [ 5 ]


COVID-19 can lead to reduced testosterone production and testicular abnormalities due to changes in the secretion of  gonadotropins , which are hormones involved in regulating testosterone production. These hormonal effects may be due to inflammation and oxidative stress caused by COVID-19. This might inform whether healthcare providers decide to monitor those who have survived COVID-19 for hormonal changes and potential fertility issues. [ 8 ] [ 18 ]


Orchitis , or inflammation of the testicles due to a bacterial or viral infection, can lead to testicular atrophy. [ 9 ]   Mumps  has historically been significantly associated with orchitis and testicular atrophy, but has become rare in countries that have high mumps vaccination rates. [ 9 ]


Varicoceles  and  testicular torsion  are conditions in which direct damage to the testicles can potentially lead to testicular atrophy. [ 6 ] [ 7 ]  Varicoceles are pooling of blood in the veins that deliver blood away from the testicles and are relatively common, occurring in approximately 15% of adolescent and adults with testicles. [ 7 ]  Currently, it is not clearly established how often varicoceles actually become a direct cause of issues related to fertility. [ 7 ]  Testicular torsion is the twisting of the testicle within the scrotum and can rapidly result in damage due to interruption in blood flow to the affected testicle. [ 6 ]  Unlike varicoceles, [ 19 ]  testicular torsion is considered a medical emergency. [ 6 ]


There is a possible correlation of cystic fibrosis and its impact to bilateral testicular atrophy. Cystic fibrosis is a disease which causes mucus buildup in various organs. [ 20 ]  Evidence has shown that cystic fibrosis affects multiple systems in the human body, including the reproductive system. Around 97-98% of people with cystic fibrosis who have testicles are infertile due to a missing vas deferens, the tube in the male reproductive system that carries sperm out of the testes. [ 21 ] [ 22 ]  Additionally, cystic fibrosis can result in the atrophy of male reproductive organs by causing dehydrated secretions. In recent times a connection to  H63D syndrome  was found.


A healthcare provider may initially assess size and shape as well as firmness and texture of the testicles. [ 19 ] [ 7 ]


Ultrasonography  is used to detect testicular volume. Testicular volume measured to be less than 12 mL is a sign of testicular atrophy. [ 10 ]  In addition, testicular atrophy can be recognized as greater than 50% loss of testicular volume or a post-operative testicle with less than 25% of the volume of the opposite testicle. [ 23 ]  Online calculators have been developed to estimate testicular volume based on sonographic measurements. [ 24 ]


Assessment of testicular function is also dependent on lab tests. Low  testosterone  is a potential cause of testicular atrophy, and laboratory values of blood samples can confirm low free or bioavailable testosterone. [ 25 ]


Due to the high levels of oxidative stress in the semen, there may also be higher levels of sperm DNA fragmentation for people with varicoceles. In some cases, people with testicular damage who do not undergo repair of the varicoceles will have testicular atrophy. [ 26 ]


Treatment with  selective estrogen receptor modulators (SERMs)  alone or in addition to self-administered injections of  hCG  aim to correct hormonal imbalances caused by anabolic steroid use and can help prevent or reverse testicular atrophy for some people. [ 4 ]


People who have testicular atrophy due to testicular torsion are immediately referred to surgery regardless of the ultrasound findings, since delays rapidly decrease the rate of recovery. The consequences of not treating will result in decreased fertility and may result in the need of an  orchiectomy , a surgical procedure to remove one or both testicles. [ 27 ]  While immediate treatment can reduce the recovery time for the testes, there is still a chance of the testes to undergo atrophy a second time. Performance of an orchiectomy on individuals diagnosed with testicular atrophy has a possible negative impact on their testosterone levels in the long term. As a result, these individuals are typically monitored for the reoccurrence of testicular atrophy and low testosterone levels. [ 28 ]


In addition to drug therapies and surgical interventions to treat testicular atrophy, lifestyle modifications might also be recommended by healthcare providers. [ 29 ]  Most lifestyle modifications target factors that contribute to infertility in men. Limiting or abstaining from alcohol intake, smoking, and drugs such as anabolic steroids, cannabis, or opioids can help with infertility. Additionally, diet modifications might be encouraged to reach a more balanced diet, such as a higher intake of fish, fruits, vegetables, nuts, seeds, whole grains, and healthier oils, such as olive oil and canola oil. [ 30 ]  Reducing intake of processed meats, and trans fats can also lead to improved fertility outcomes. Poor diet can otherwise lead to oxidative stress, which causes sperm damage, leading to lower testicular volume and lower sperm quality. Ensuring enough vitamin and mineral intake might also be recommended, since omega-3 fatty acids, antioxidant vitamins, zinc, and selenium might help reduce the damage by oxidative stress and reduce inflammation. Zinc intake can be boosted with meats and nuts, and selenium intake can be boosted with whole grains. [ 31 ]


Alkalinizing agents  are drugs used to manage disorders associated with low pH.  For example, they may be used to treat  acidosis  due to  kidney failure .


Used for  oral  or  parenteral  therapy,  sodium bicarbonate  is the commonly preferred alkalinizing agent. [ 1 ]  Others include  potassium citrate ,  calcium carbonate ,  sodium lactate  and  calcium acetate . [ 2 ]


An  antidiuretic  is a  substance  that helps to control  fluid balance  in an  animal 's body by reducing  urination , [ 1 ]  opposing  diuresis . [ 2 ]  Its effects are opposite that of a  diuretic . The major  endogenous  antidiuretics are  antidiuretic hormone  (ADH; also called vasopressin) and  oxytocin . Both of those are also used  exogenously  as  medications  in people whose bodies need extra help with fluid balance via suppression of diuresis. In addition, there are various other antidiuretic drugs, some  molecularly  close to ADH or oxytocin and others not. Antidiuretics reduce urine volume, particularly in  diabetes insipidus  (DI), which is one of their main  indications .


The antidiuretic hormone class includes  vasopressin  (ADH),  argipressin ,  desmopressin ,  lypressin ,  ornipressin ,  oxytocin , and  terlipressin . Miscellaneous others include  chlorpropamide  and  carbamazepine .


This  hormonal preparation  article is a  stub . You can help Wikipedia by  expanding it .


Menotropin  (also called  human menopausal gonadotropin  or  hMG ) is a  hormonally  active medication for the treatment of  fertility disturbances . Frequently the plural is used as the medication is a mixture of  gonadotropins . Menotropins are extracted from the urine of  postmenopausal  women. [ 1 ]


Urine of postmenopausal women reflects the hypergonadotropic state of  menopause  -levels of  follicle stimulating hormone  (FSH) and  luteinizing hormone  (LH) are high - and contain a mixture of these gonadotropins. [ 2 ] [ 3 ] [ 4 ]  Other  protein  substances may be present, including small amounts of  human chorionic gonadotropin  (hCG). [ 1 ]  In 1949 Piero Donini found a relatively simple method to extract gonadotropins from urine of postmenopausal women. [ 4 ] [ 5 ]   Menotropins were successfully introduced into clinical use by Bruno Lunenfeld in 1961. [ 4 ]  While earlier menotropin medications contained FSH and LH at a 1:1 ratio, the recognition that it is FSH that is critical for follicle stimulation has led to development of newer preparations that contain a much higher FSH/LH ratio, Fertinex being an example. [ 4 ]


Menotropin preparations are designed for use in selected women where they stimulate the ovaries to mature follicles, thus making them more fertile. They are administered by typically daily injection, intramuscularly or subcutaneously, for about ten days under close supervision to adjust dose and duration of therapy. They can also be used in  hypogonadal  men to stimulate sperm production.


Human urinary-derived menotropin preparations are exposed to the theoretical risk of infection from menopausal donors of urine. Nevertheless, the failure to irrefutably demonstrate infectivity following intracerebral inoculation with urine from  transmissible spongiform encephalopathy  (TSE)-infected hosts suggests that the risk associated with products derived from urine is merely theoretical. [ 6 ]


Recombinant  gonadotropins have to a large degree replaced hMG in fertility treatments. The recombinant process allows for the production of pure FSH or LH not "contaminated" by other proteins that may be present after urinary extraction. While some head-on studies seem not to suggest that "pure FSH" gives better results than hMG, [ 7 ]  others claim that recombinant FSH is more efficient and reduces costs. [ 8 ]  A  Cochrane Collaboration  analysis did not reveal major differences in clinical outcomes when comparing urinary versus recombinant FSH. [ 9 ]


The Practice Committee of the  American Society for Reproductive Medicine  reported: [ 10 ]   “Compared with earlier crude animal extracts, modern highly purified urinary and recombinant gonadotropin products have clearly superior quality, specific activity, and performance. There are no confirmed differences in safety, purity, or clinical efficacy among the various available urinary or recombinant gonadotropin products.”


A number of drug companies have and had marketed hMG preparations that include: [ 11 ]


1-Methylnicotinamide  ( 1-MNA,   trigonellamide ) is a prototypic organic  cation . [ 1 ]  1-Methylnicotinamide is the methylated amide of  Nicotinamide  (niacinamide, vitamin B 3 ).


1-Methylnicotinamide is an endogenic substance that is produced in the liver when  Nicotinamide  is metabolized. It is a typical  substance secreted in the kidney . It participates in the nicotinamide salvage pathway within the NAD +  (nicotinamide adenine dinucleotide) metabolic pathway, thereby contributing to optimizing NAD +  levels. [ 2 ]


To date, the highest natural concentration of 1-methylnicotinamide has been found in the alga  Undaria pinnatifida  (3.2 mg/100 g of dried algae) and green tea leaves (3 mg/100 g of product). Other products with notable 1-MNA content include celery (1.6 mg/100 g of product), Chinese black mushrooms (shiitake, 1.3 mg/100 g), and fermented soybeans (natto, 1.0 mg/100 g). [ 3 ]


1-Methylnicotinamide can be produced in the liver by  nicotinamide  N -methyltransferase  (NNMT). The reaction takes place during the metabolism of NAD +  ( nicotinamide adenine dinucleotide ). NNMT is also present in brain tissue, adipose tissue, muscle tissue, kidneys, and skin. [ 4 ] [ 5 ]


NNMT  (nicotinamide  N -methyltransferase) is an  enzyme  that in humans is encoded by the  NNMT   gene . [ 6 ]   NNMT catalyzes the  methylation  of  nicotinamide  and similar compounds using the methyl donor  S -adenosyl methionine  (SAM-e) to produce  S -adenosyl- L -homocysteine  (SAH) and 1-methylnicotinamide. [ 7 ]   NNMT  is highly  expressed  in the human liver. [ 7 ]


Scientific research highlights numerous therapeutic and health-promoting properties of 1-MNA, including vascular protective, [ 8 ] [ 9 ]  anticoagulant, [ 10 ]  anti-atherosclerotic, [ 11 ]  anti-inflammatory, [ 12 ] [ 13 ] [ 14 ]  neuroprotective, [ 15 ]  and endurance-enhancing effects. [ 16 ]


1-MNA exerts beneficial effects on blood vessels through its action on the vascular endothelium. It improves the bioavailability of nitric oxide (NO), which is crucial for vasodilation, and regulates the activity of endothelial nitric oxide synthase (eNOS), the enzyme responsible for NO synthesis. [ 8 ] [ 9 ]


These effects have been demonstrated in both in vivo and in vitro studies. Oral administration of 1-MNA has been shown to increase the diameter of the brachial artery (as measured by flow-mediated dilation, FMD) and stimulate NO release from human endothelial cells in both healthy individuals and those with hypercholesterolemia increased. [ 9 ]


Additionally, in cases of vascular dysfunction (e.g., hypertriglyceridemia or diabetes), 1-MNA restored normal NO-dependent vasodilation. [ 8 ]  By increasing NO bioavailability, 1-MNA may counteract endothelial dysfunction, support endothelial regeneration, and improve vascular function, particularly in the context of cardiovascular risk. [ 8 ] [ 9 ]


1-Methylnicotinamide is an endogenous activator of  prostacyclin synthesis  and can therefore regulate thrombolytic [ check spelling ]  and inflammatory processes in the cardiovascular system. [ 8 ]  It inhibits platelet-dependent  thrombosis  through a mechanism involving [ 10 ]   cyclooxygenase-2  and prostacyclin (PGI 2 ) and increases nitric oxide bioavailability in the  endothelium . [ 9 ] [ 7 ]  Endogenous prostacyclin ( PGI 2 ) plays a critical role in preventing platelet aggregation and thrombus formation. A deficiency in PGI 2  can lead to increased platelet aggregation and arterial thrombi.


1-MNA exhibits anti-atherosclerotic and anti-inflammatory properties by improving the prostacyclin- and NO-dependent secretory function of the vascular endothelium, inhibiting platelet activation, reducing inflammation within atherosclerotic plaques, and lowering systemic inflammation and TNF-α levels. [ 11 ]