Some women with connective tissue disorders are predisposed to developing anterior vaginal wall collapse. Up to one third of women with  Marfan syndrome  have a history of vaginal wall collapse.  Ehlers-Danlos  syndrome in women is associated with a rate of 3 out of 4. [ 6 ]


Risk factors for developing a cystocele are:


Connective tissue disorders predispose women to developing cystocele and other pelvic organ prolapse. The tissues tensile strength of the vaginal wall decreases when the structure of the collagen fibers change and become weaker. [ 6 ]


There are two types of cystocele. The first is distension. This is thought to be due to the overstretching of the vaginal wall and is most often associated with aging, menopause and vaginal delivery. It can be observed when the  rugae  are less visible or even absent. The second type is displacement. Displacement is the detachment or abnormal elongation of supportive tissue. [ 25 ]


The initial assessment of cystocele can include a  pelvic exam  to evaluate leakage of urine when the women is asked to bear down or give a strong cough ( Valsalva maneuver ), and the anterior vaginal wall measured and evaluated for the appearance of a cystocele. [ 26 ] [ 27 ]  If a woman has difficulty emptying her bladder, the clinician may measure the amount of urine left in the woman's bladder after she urinates called the postvoid residual. This is measured by  ultrasound . A  voiding cystourethrogram  is a test that involves taking x-rays of the bladder during urination. This  x-ray  shows the shape of the bladder and lets the doctor see any problems that might block the normal flow of urine. [ 1 ]  A urine culture and sensitivity test will assess the presence of a urinary tract infection that may be related to urinary retention. [ 12 ]  Other tests may be needed to find or rule out problems in other parts of the urinary system. [ 1 ]  Differential diagnosis will be improved by identifying possible inflammation of the  Skene's glands  and  Bartholin glands . [ 28 ]


A number of scales exist to grade the severity of a cystocele. [ citation needed ]


The  pelvic organ prolapse quantification  (POP-Q) assessment, developed in 1996, quantifies the descent of the cystocele into the vagina. [ 6 ] [ 13 ]  The POP-Q provides reliable description of the support of the anterior, posterior and apical vaginal wall. It uses objective and precise measurements to the reference point, the  hymen . Cystocele and prolapse of the vagina from other causes is staged using POP-Q criteria can range from good support (no descent into the vagina) reported as a POP-Q stage 0 or I to a POP-Q score of IV which includes prolapse beyond the hymen. It also used to quantifies the movement of other structures into the vaginal  lumen  and their descent. [ 6 ] [ 13 ]


The Baden–Walker Halfway Scoring System is used as the second most used system and assigns the classifications as mild (grade 1) when the bladder droops only a short way into the vagina; (grade 2) cystocele, the bladder sinks far enough to reach the opening of the vagina; and (grade 3) when the bladder bulges out through the opening of the vagina. [ 1 ] [ 29 ]


Cystocele can be further described as being apical, medial, or lateral. [ 30 ]


Apical cystocele  is located upper third of the vagina. The structures involved are the  endopelvic fascia  and  ligaments . The  cardinal ligaments  and the  uterosacral ligaments  suspend the upper vaginal-dome. The cystocele in this region of the vagina is thought to be due to a cardinal ligament defect. [ 16 ] [ 25 ]


Medial cystocele  forms in the mid-vagina and is related to a defect in the suspension provided by to a sagittal suspension system defect in the uterosacral ligaments and  pubocervical fascia . The pubocervical fascia may thin or tear and create the cystocele. An aid in diagnosis is the creation of a 'shiny' spot on the epithelium of the vagina. This defect can be assessed by  MRI . [ 16 ] [ 25 ]


Lateral cystocele  forms when both the pelviperineal muscle and its ligamentous–fascial develop a defect. The ligamentous– fascial creates a 'hammock-like' suspension and support for the lateral sides of the vagina. Defects in this lateral support system results in a lack of bladder support. Cystocele that develops laterally is associated with an anatomic imbalance between anterior vaginal wall and the  arcus tendineus fasciae  pelvis – the essential ligament structure. [ 16 ] [ 25 ]


Cystocele may be mild enough not to result in symptoms that are troubling to a woman. In this case, steps to prevent it from worsening include:


Treatment options range from no treatment for a mild cystocele to  surgery  for a more extensive cystocele. [ 1 ]  If a cystocele is not bothersome, the clinician may only recommend avoiding heavy lifting or straining that could cause the cystocele to worsen. If symptoms are moderately bothersome, the doctor may recommend a  pessary , a device placed in the vagina to hold the bladder in place and to block protrusion. [ 12 ] [ 23 ]  Treatment can consist of a combination of non-surgical and surgical management. Treatment choice is also related to age, desire to have children, severity of impairment, desire to continue sexual intercourse and other diseases that a woman may have. [ 6 ]


Cystocele is often treated by non-surgical means:


The surgery to repair the anterior vaginal wall may be combined with other procedures that will repair the other points of pelvic organ support such as anterior-posterior repair and anterior colporrhaphy. [ 12 ]  Treatment of cystocele often accompanies the more invasive hysterectomy. [ 32 ]  Since the failure rate in cystocele repair remains high, additional surgery may be needed. [ 13 ]  Women who have surgery to repair a cystocele have a 17% of needing another operation within the next ten years. [ 33 ]


The surgical treatment of cystocele will depend on the cause of the defect and whether it occurs at the top (apex), middle, or lower part of the anterior vaginal wall. The type of surgery will also depend on the type of damage that exists between supporting structures and the vaginal wall. [ 2 ]  One of the most common surgical repairs is  colporrhaphy . [ 32 ]  This surgical procedure consists of making a longitudinal folding of the vaginal tissue, suturing it into place and creating a stronger point of resistance to the intruding bladder wall.  Surgical mesh  is sometimes used to strengthen the anterior vaginal wall. [ 6 ]  It has a 10–50% failure rate. [ 34 ] [ 32 ]  In some cases a surgeon may choose to use  surgical mesh  to strengthen the repair. [ 32 ]


During surgery, the repair of the vaginal wall consists of folding over and then suturing the existing tissue between the vagina and bladder to strengthen it. [ 1 ] [ 11 ]  This tightens the layers of tissue to promote the replacement of the pelvic organs into their normal place. The surgery also provides more support for the bladder. This surgery is done by a surgeon specializing in gynecology and is performed in a hospital.  Anesthesia  varies according to the needs of each woman. Recovery may take four to six weeks. [ 1 ]  Other surgical treatment may be performed to treat cystocele. Support for the vaginal wall is accomplished with the paravaginal defect repair. This is a surgery, usually  laproscopic , that is done to the ligaments and fascia through the abdomen. The lateral ligaments and supportive structures are repaired, sometimes shortened to provide additional support to the vaginal wall. [ 32 ]


Sacrocolpopexy  is a procedure that stabilizes the vaginal vault (the uppermost portion of the vagina) and is often chosen as the treatment for cystocele, especially if previous surgeries were not successful. The procedure consists of attaching the vaginal vault to the sacrum. It has a success rate of 90%. [ 32 ]  Some women choose not to have surgery to close the vagina. This surgery, called  colpocleisis , treats cystocele by closing the vaginal opening. This can be an option for women who no longer want to have vaginal intercourse. [ 22 ]


If an  enterocele / sigmoidocele , or prolapse of the rectum/colon, is also present, the surgical treatment will take this concurrent condition into account while planning and performing the repairs. [ 2 ]  Estrogen that is administered vaginally before surgical repair can strengthen the vaginal tissue providing a more successful outcome when mesh or sutures are used for the repair. Vaginal thickness increases after estrogen therapy. [ 33 ]  Another review on the surgical management of cystocele describes a more successful treatment that more strongly attaches the ligaments and fascia to the vagina to lift and stabilize it. [ 35 ]


Post surgical complications can develop. The complications following surgical treatment of cystocele are:


After surgery, a woman is instructed to restrict her activities and monitor herself for signs of infection such as an elevated temperature, discharge with a foul odor and consistent pain. Clinicians may recommend that sneezing, coughing, and constipation are to be avoided. Splinting the abdomen while coughing provides support to an incised area and decreases pain on coughing. [ 12 ]  This is accomplished by applying gentle pressure to the surgical site for bracing during a cough. [ 36 ] [ 37 ]


Recurrent surgery on the pelvic organs may not be due to a failure of the surgery to correct the cystocele. Subsequent surgeries can be directly or indirectly relating to the primary surgery. [ 13 ]  Prolapse can occur at a different site in the vagina. Further surgery after the initial repair can be to treat complications of mesh displacement, pain, or bleeding. Further surgery may be needed to treat incontinence. [ 13 ]


One goal of surgical treatment is to restore the vagina and other pelvic organs to their anatomically normal positions. This may not be the outcome that is most important to the woman being treated who may only want relief of symptoms and an improvement in her quality of life. The International Urogynecological Association (IUGA) has recommended that the data collected regarding the success of cystocele and pelvic organ repairs include the presence or absence of symptoms, satisfaction and Quality of Life. Other measures of a successful outcome should include perioperative data, such as operative time and hospital stay.  Standardized Healthcare Quality of Life  should be part of the measure of a successful resolution of cystocele. Data regarding short- and long-term complications is included in the recommendations of the IUGA to better assess the risk–benefit ratio of each procedure. [ 13 ]  Current investigations into the superiority of using biological grafting versus native tissue or surgical mesh indicates that using grafts provides better results. [ 38 ]


A large study found a rate of 29% over the lifetime of a woman. Other studies indicate a recurrence rate as low as 3%. [ 13 ]


In the US, greater than 200,000 surgeries are performed each year for pelvic organ prolapse and 81% of these are to correct cystocele. [ 14 ] [ 11 ]  Cystocele occurs most frequently compared to the prolapse of other pelvic organs and structure. [ 13 ] [ 14 ]  Cystocele is found to be three times as common as vaginal vault prolapse and twice as often as posterior vaginal wall defects. The incidence of cystocele is around 9 per 100 women-years. The highest incidence of symptoms occurs between ages of 70 and 79 years. Based on population growth statistics, the number of women with prolapse will increase by a minimum of 46% by the year 2050 in the US. Surgery to correct prolapse after hysterectomy is 3.6 per 1,000 women-years. [ 13 ]


Notable is the mention of cystocele in many older cultures and locations. [ 39 ]  In 1500 B.C. Egyptians wrote about the "falling of the womb". In 400 B.C. a Greek physician documented his observations and treatments:


"After the patient had been tied to a ladder-like frame, she was tipped upward so that her head was toward the bottom of the frame. The frame was then moved upward and downward more or less rapidly for approximately 3–5 min. As the patient was in an inverted position, it was thought that the prolapsing organs of the genital tract would be returned to their normal position by the force of gravity and the shaking motion." [ 39 ]


Hippocrates  had his own theories regarding the cause of prolapse. He thought that recent childbirth, wet feet, 'sexual excesses', exertion, and fatigue may have contributed to the condition.  Polybus , Hippocrates's son-in-law, wrote: "a prolapsed uterus was treated by using local astringent lotions, a natural sponge packed into the vagina, or placement of half a pomegranate in the vagina." In 350 A.D., another practitioner named Soranus described his treatments which stated that the pomegranate should be dipped into vinegar before insertion. Success could be enhanced if the woman was on bed rest and reduced intake of fluid and food. If the treatment was still not successful, the woman's legs were tied together for three days. [ 39 ]


In 1521,  Berengario da Carpi  performed the first surgical treatment for prolapse. This was to tie a rope around the prolapse, tighten it for two days until it was no longer viable and cut it off. Wine, aloe, and honey were then applied to the stump. [ 39 ]


In the 1700s, a Swiss gynecologist, Peyer, published a description of a cystocele. He was able to describe and document both cystocele and uterine prolapse. In 1730, Halder associated cystocele with childbirth. During this same time, efforts began to standardize the terminology that is still familiar today. In the 1800s, the surgical advancements of anesthesia, suturing, suturing materials and acceptance of  Joseph Lister's  theories of  antisepsis  improved outcomes for women with cystocele. The first surgical techniques were practiced on female cadavers. In 1823, Geradin proposed that an incision and resection may provide treatment. In 1830, the first dissection of the vagina was performed by Dieffenbach on a living woman. In 1834, Mendé proposed that dissecting and repair of the edges of the tissues could be done. In 1859, Huguier proposed the amputation of the cervix was going to solve the problem for elongation. [ 39 ]


In 1866, a method of correcting a cystocele was proposed that resembled current procedures. Sim subsequently developed another procedure that did not require the full-thickness dissection of the vaginal wall. In 1888, another method of treating anterior vaginal wall Manchester combined an anterior vaginal wall repair with an amputation of the cervix and a perineorrhaphy. In 1909, White noted the high rate of recurrence of cystocele repair. At this time it was proposed that reattaching the vagina to support structures was more successful and resulted in less recurrence. This same proposal was proposed again in 1976 but further studies indicated that the recurrence rate was not better. [ 39 ]


In 1888, treatments were tried that entered the abdomen to make reattachments. Some did not agree with this and suggested an approach through the  inguinal canal . In 1898, further abdominal approaches were proposed. No further advances have been noted until 1961 when reattachment of the anterior vaginal wall to  Cooper's ligament  began to be used. Unfortunately, posterior vaginal wall prolapse occurred in some patients even though the anterior repair was successful. [ 39 ]


In 1955, using mesh to support pelvic structures came into use. In 1970, tissue from pigs began to be used to strengthen the anterior vaginal wall in surgery. Beginning in 1976, improvement in suturing began along with the surgical removal of the vagina being used to treat prolapse of the bladder. In 1991, assumptions about the detailed anatomy of the pelvic support structures began to be questioned regarding the existence of some pelvic structures and the non-existence of others. More recently, the use of stem cells, robot-assisted laparoscopic surgery are being used to treat cystocele. [ 39 ]


Dapoxetine , sold under the brand name  Priligy  among others, is a  selective serotonin reuptake inhibitor  (SSRI) used for the treatment of  premature ejaculation  (PE) in men ages 18 to 64 years old. [ 3 ] [ 4 ] [ 5 ]  Dapoxetine works by inhibiting the  serotonin transporter , increasing serotonin's action at the postsynaptic cleft, and as a consequence promoting ejaculatory delay. [ 6 ]  As a member of the SSRI family, dapoxetine was initially created as an  antidepressant . However, unlike other SSRIs, dapoxetine is absorbed and eliminated rapidly in the body. Its fast-acting property makes it suitable for the treatment of PE, but not as an antidepressant. [ 7 ]


Originally created by  Eli Lilly  pharmaceutical company, dapoxetine was sold to  Johnson & Johnson  in 2003 and submitted as a  New Drug Application  to the US Food and Drug Administration  (FDA) for the treatment of PE in 2004. [ 8 ]  Dapoxetine is sold in several European and Asian countries, and in Mexico. In the US, dapoxetine has been in phase III development. In May 2012, US-based Furiex Pharmaceuticals reached an agreement with ALZA Corp and Janssen Pharmaceuticals to market dapoxetine in the United States, Japan, and Canada, while selling the rights to market the drug in Europe, most of Asia, Africa, Latin America, and the Middle East to  Menarini . [ 9 ]


Randomized, double-blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE. [ 10 ]  Different dosages have different impacts on different types of PE. Dapoxetine 60 mg significantly improves the mean  intravaginal ejaculation latency time  (IELT) compared to that of dapoxetine 30 mg in men with lifelong PE, but no difference is seen in men with acquired PE. [ 11 ]  Dapoxetine, given 1–3 hours before sexual episode, prolongs IELT and increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress and interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition. [ 12 ]
With no drug approved specifically for treatment for PE in the US and some other countries, other SSRIs such as  fluoxetine ,  paroxetine ,  sertraline ,  fluvoxamine , and  citalopram  have been used off-label to treat PE. Waldinger's meta-analysis shows that the use of these conventional antidepressants increases IELT two- to nine-fold above baseline, compared to three- to eight-fold when dapoxetine is used. [ 11 ]  However, these SSRIs may need to be taken daily  to achieve meaningful efficacy, and their comparatively longer half-lives increase the risk of drug accumulation and a corresponding increase of adverse effects such as reduced libido. [ 13 ]  Dapoxetine, though, is generally categorized as a fast-acting SSRI. It is more rapidly absorbed and mostly eliminated from the body within a few hours. These pharmacokinetics are more favorable in that they might minimize drug accumulation in the body, habituation, and side effects. [ 7 ]


Although it was initially thought of as unsuccessful in its intended use as an antidepressant, dapoxetine has been more recently investigated as a possible aid to one approach to depression treatment focused on stress reduction, based on an animal model of depression. [ 14 ] [ 15 ]


Dapoxetine should not be used in men with moderate to severe hepatic impairment and in those receiving CYP3A4 inhibitors such as  ketoconazole ,  ritonavir , and  telithromycin . Dapoxetine also cannot be used in patients with heart failure, permanent pacemaker, or other significant ischemic heart disease. Caution is advised in men receiving  thioridazine ,  monoamine oxidase inhibitors , SSRIs,  serotonin-norepinephrine reuptake inhibitors , or  tricyclic antidepressants . If a patient stops taking one of these drugs, he should wait for 14 days before taking dapoxetine. If a patient stops taking dapoxetine, he should wait for 7 days before receiving these drugs. [ 6 ]


The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and  insomnia . [ 16 ] [ 17 ]  Discontinuation rates due to adverse effects and costs are very high. A recent study in Asia showed that cumulative discontinuation rates within one year are as high as 87%. [ 18 ]  Unlike other SSRIs used to treat depression, which have been associated with high incidences of  sexual dysfunction , [ 19 ]  dapoxetine is associated with low rates of sexual dysfunction. Taken as needed, dapoxetine has very mild adverse effects of decreased libido (<1%) and erectile dysfunction (<4%). [ 7 ]


No case of drug overdose has been reported during clinical trials. [ 20 ]


Many men who have PE also suffer from  erectile dysfunction  (ED). Treatment for these patients should consider the drug–drug interaction between dapoxetine and PDE5 inhibitors such as  tadalafil  (Cialis) or  sildenafil  (Viagra). In Dresser study (2006), plasma concentration of 24 subjects was obtained. Half of the sample pool were treated with dapoxetine 60 mg plus tadalafil 20 mg; the other half were treated with dapoxetine 60 mg plus sildenafil 100 mg. These plasma samples were then analyzed using liquid chromatography-tandem mass spectrometry. The results showed that dapoxetine does not alter the pharmacokinetic of tadalafil or sildenafil. [ 3 ]


Alcohol  does not affect the pharmacokinetics of dapoxetine when taking concurrently. [ 21 ]


The mechanism through which dapoxetine affects premature ejaculation is still unclear, but dapoxetine is presumed to work by inhibiting  serotonin transporter  (SERT) and subsequently increasing serotonin's action at pre- and postsynaptic receptors. [ 22 ]  Human ejaculation is regulated by various areas in the  central nervous system  (CNS). [ 23 ]  The ejaculatory pathway originates from spinal reflex at the thoracolumbar and lumbosacral level of spinal cord activated by stimuli from male genitalia. These signals are passed on to the  brain stem , which then is influenced by a number of nuclei in the brain such as medial preoptic and paraventricular nuclei. [ 24 ]  Clement's study performed on anaesthetized male rats showed that acute administration of dapoxetine inhibits ejaculatory expulsion reflex at supraspinal level by modulating activity of lateral paragigantocellular nucleus (LPGi) neurons. These effects cause an increase in pudendal motoneuron reflex discharge (PMRD) latency, though whether dapoxetine acts directly on LPGi or on the descending pathway in which LPGi located is unclear. [ 25 ]


Dapoxetine is a white, powdery, water-insoluble substance. Taken one to three hours before sexual activity, it is rapidly absorbed in the body. Its  maximum plasma concentration  (C max ) is reached one to two hours after oral administration. The C max  and  AUC  (area under the plasma vs. time curve) is dose dependent. The C max  and Tm (time needed to obtain the maximum plasma concentration) after single doses of dapoxetine 30 mg and 60 mg are 297 and 498 ng/ml at 1.01 and 1.27 hours, respectively.
A high-fat meal does reduce the C max  slightly, but it is insignificant. In fact, food does not alter dapoxetine pharmacokinetics. It can be taken with or without food. [ 26 ]


Dapoxetine is absorbed and distributed rapidly in the body. Greater than 99% of dapoxetine is bound to the plasma protein. The mean steady-state volume is 162 L. Its initial half-life is 1.31 hours (30 mg dose) and 1.42 hours (60 mg dose), and its terminal half life is 18.7 hours (30 mg dose) and 21.9 hours (60 mg dose). [ 27 ]


Dapoxetine is  metabolized  extensively in the liver and kidney by multiple  enzymes  such as CYP2D6, CYP3A4, and flavin monooxygenase 1. The major product at the end of the metabolic pathway is circulating dapoxetine N-oxide, which is a weak SSRI and contributes no clinical effect. The other products presented less than 3% in the plasma are desmethyldapoxetine and didesmethydapoxetine. Desmethyldapoxetine is roughly equipotent to dapoxetine. [ 28 ]


The  metabolites  of dapoxetine are eliminated rapidly in the urine with a terminal half-life of 18.7 and 21.9 hours for a single dose of 30 mg and 60 mg, respectively. [ 21 ]


The cardiovascular safety profile of dapoxetine has been studied extensively during the  drug development . Phase I trials showed that dapoxetine had neither clinically significant electrocardiographic effects nor delayed repolarization effects, with dosing up to four-fold greater than the maximum recommended dosage, which is 60 mg. Phase III studies in men with PE showed a safety and well tolerated profile of dapoxetine with dosing of 30 and 60 mg. No cardiovascular adverse had been found. [ 29 ]


Studies of SSRIs in patients with major  psychiatric disorders  prove that SSRIs are potentially associated with certain neurocognitive adverse effects such as  anxiety ,  akathisia ,  hypomania , changes in mood, or suicidal thought. [ 30 ] [ 31 ]  No study on the effects of SSRIs in men with PE has been done.  McMahon's study in 2012 showed that dapoxetine has no effect on mood and is not associated with anxiety or suicidality. [ 32 ]


The incidence of  antidepressant discontinuation syndrome  symptoms in men using dapoxetine to treat PE has been described by reviewers as low or no different from the incidence of such symptoms in men withdrawn from placebo treatment. [ 33 ] [ 34 ]  The lack of chronic serotonergic stimulation with on-demand dapoxetine minimizes the potentiation action of serotonin at synaptic cleft, thus decreasing the risk of discontinuation symptoms. [ 35 ]


Currently, very few methods are used to synthesize ( S )-dapoxetine. This novel approach consists of only six steps in which three main steps are shown above. The initial reactant is  trans -cinnamyl alcohol, which is commercially available.  Sharpless asymmetric epoxidation  and  Mitsunobu reaction  have been used to produce expected ( S )-dapoxetine. The overall yield is 35%. This method is considered a good choice compared to the known methods due to high yield and easily obtainable reactants. [ 36 ]


Dapoxetine was created by Eli Lilly and in phase I clinical trial as an antidepressant. It never worked out well as a medication for the treatment of depression, though, and was shelved for a while before subsequently developed to treat PE. In December 2003, Eli Lilly sold the patent for dapoxetine to  Pharmaceutical Product Development  (PPD) for US$65 million. Eli Lilly may also receive royalties payment from PPD if the sale exceeds a certain amount. Research into the effectiveness of dapoxetine was revisited in 2020. [ 37 ]


ALZA is the current owner of dapoxetine, but PPD will receive milestone payments and drug royalties from ALZA. If approved, dapoxetine will be marketed in the US by Ortho McNeil pharmaceutical, Inc. Ortho McNeil and Janssen-Ortho Inc, or Janssen-Cilag are all units of Johnson & Johnson.
As at 2005, dapoxetine was in phase III clinical trials, pending review by the FDA. [ 38 ]


Dapoxetine has been marketed and approved in more than 50 countries. [ 39 ]  Dapoxetine has been approved in Italy, Spain, Mexico, South Korea, and New Zealand in 2009 and 2010; marketed in Sweden, Austria, Germany, Finland, Spain, Portugal, and Italy. It has also been approved in France, Russia, Malaysia, Philippines, Argentina, and Uruguay. [ 6 ]


William P. Didusch  (1895-1981) was a  scientific illustrator  known for his work for the  American Urological Association . [ 1 ] [ 2 ]


Ejaculation  is the discharge of  semen  (the  ejaculate ; normally containing  sperm ) from the  penis  through the  urethra . [ 1 ] [ 2 ] [ 3 ]  It is the final stage and natural objective of male  sexual stimulation , and an essential component of  natural conception . After forming an  erection , many men emit  pre-ejaculatory fluid  during stimulation prior to ejaculating. Ejaculation involves involuntary  contractions  of the  pelvic floor  and is normally linked with  orgasm . It is a normal part of male  human sexual development .


It can occur spontaneously during  sleep  (a  nocturnal emission  or "wet dream"). In rare cases, ejaculation occurs because of  prostatic  disease.  Anejaculation  is the condition of being unable to ejaculate.  Dysejaculation  is an ejaculation that is painful or uncomfortable.  Retrograde ejaculation  is the backward flow of semen into the  bladder  rather than out of the urethra.  Premature ejaculation  happens shortly after initiating sexual activity, and hinders prolonged  sexual intercourse . A  vasectomy  alters the composition of the ejaculate as a form of  birth control .


The normal precursor to ejaculation is  sexual arousal  of the male, leading to the  erection  of the  penis , though not all arousals or erections lead to ejaculation, and ejaculation does not require erection. Penile sexual stimulation during  masturbation  or  vaginal ,  anal ,  oral ,  manual , or  non-penetrative  sexual activity may provide the necessary stimulus for a man to achieve  orgasm  and ejaculation. With regard to  intravaginal ejaculation latency , men typically reach orgasm five to seven minutes after the start of penile-vaginal  intercourse , taking into account their desire and that of their partners, but 10 minutes is also a common intravaginal ejaculation latency. [ 4 ] [ 5 ]  Prolonged stimulation either through  foreplay  (kissing, petting and direct stimulation of erogenous zones before penetration during intercourse) or stroking (during masturbation) leads to adequate arousal and production of  pre-ejaculatory fluid . Infectious agents (including  HIV ) can be present in pre-ejaculate. [ 6 ]


Once the penis has achieved sufficient stimulation for the man to reach orgasm, ejaculation begins. [ 7 ]  The initial stage of ejaculation, called emission, is controlled by a reflex in the sympathetic spinal cord. Sperm undergo their final developmental changes within the  epididymis , where they are held until being ejaculated. [ 8 ]


Ejaculation reaches its peak in the expulsion phase, which involves the discharge of semen from the urethral opening. This ejection is driven by coordinated contractions of the pelvic muscles, including the  bulbospongiosus  and  pubococcygeus  muscles. For the semen to be expelled out of the penis, the bladder neck stays shut while the external  urethral sphincter  is relaxed. These rhythmic contractions are part of the male orgasm [ 9 ]  under the control of a  spinal reflex  at the level of the  spinal nerves  S2–4 via the  pudendal nerve . Although the external sphincter and pelvic muscles can be voluntarily controlled, any voluntary control during semen expulsion is not evident. The expulsion phase is considered an extension of the emission phase, triggered by reaching a certain level of spinal nerve activation. [ 10 ]  The typical male orgasm lasts several seconds.


Premature ejaculation  is when ejaculation occurs before it is desired. Otherwise, if a man is unable to ejaculate after prolonged sexual stimulation in spite of his desire, it is called  delayed ejaculation  or  anorgasmia . An orgasm that is not accompanied by ejaculation is known as a  dry orgasm .


At start of orgasm, pulses of semen begin to flow from the urethra, reach a peak of discharge and then diminish in flow. The typical orgasm consists of 10 to 15 contractions, although the man may not be consciously aware of so many. After the first contraction, ejaculation continues to completion involuntarily. During this stage ejaculation cannot be stopped. The rate of contractions gradually slows throughout the orgasm. Initial contractions occur on average every 0.6 seconds with an increasing increment of 0.1 seconds per contraction. Contractions of most men proceed at regular rhythmic intervals through their duration. Many men also experience irregular contractions at the end of the orgasm. [ 11 ]


Ejaculation usually begins during the first or second contraction of orgasm. For most men, the first ejection occurs during the second contraction, which is typically the largest, expelling 40% or more of total semen discharge. After this peak, the quantity of semen emitted by the penis diminishes as the contractions lessen in intensity. The muscle contractions of the orgasm can continue after ejaculation with no additional semen discharge. A small sample study of seven men showed an average of seven spurts of semen followed by an average of 10 more contractions with no semen expelled. This study also found a high correlation between number of spurts of semen and total ejaculate volume, i.e., larger semen volumes resulted from additional pulses of semen rather than larger individual spurts. [ 12 ]


Alfred Kinsey  measured the distance of ejaculation, in "some hundreds" of men. In three-quarters of men tested, ejaculate "is propelled with so little force that the liquid is not carried more than a minute distance beyond the tip of the penis." In contrast to those test subjects, Kinsey noted "In other males the semen may be propelled from a matter of some inches to a foot or two, or even as far as five or six and (rarely) eight feet". [ 13 ]   Masters and Johnson  report ejaculation distance to be no greater than 30–60 cm (12–24 in). [ 14 ]  During the series of contractions that accompany ejaculation, semen is propelled from the urethra at 500 cm/s (200 in/s), close to 18 km/h (11 mph). [ 9 ]


Most men experience a  refractory period  immediately following an orgasm, during which they are unable to achieve another erection, and a longer period before they are capable of achieving another ejaculation. During this time a male feels a deep and often pleasurable sense of relaxation, usually in the groin and thighs. The length of the refractory period varies considerably, even for a given individual. Age affects the recovery time, with younger men recovering faster than older men, though not always. [ 14 ]


Whereas some men have refractory periods of 15 minutes or more, others are able to experience sexual arousal immediately after ejaculation. A short recovery period may allow partners to continue sexual play relatively uninterrupted by ejaculation. Some men may experience their penis becoming hypersensitive to stimulation after ejaculation, which can make sexual stimulation unpleasant even while they may be sexually aroused.


Some men are able to achieve multiple orgasms, with or without the typical sequence of ejaculation and refractory period. Some of those men report not noticing refractory periods, or are able to maintain erection by "sustaining sexual activity with a full erection until they passed their refractory time for orgasm when they proceeded to have a second or third orgasm". [ 15 ]


The force and amount of semen that is ejected during ejaculation varies widely among men, containing between 0.1 and 10  milliliters [ 16 ]  (for comparison, a  teaspoon  holds 5 ml and a tablespoon, 15 ml). Adult semen volume is affected by the time that has passed since his previous ejaculation; larger semen volumes develop with longer abstinence. The duration of the stimulation leading to ejaculation can affect the volume. [ 17 ]  Abnormally low semen volume is known as  hypospermia  and abnormally high semen volume is called  hyperspermia . One possible underlying cause of low volume or complete lack of semen is  ejaculatory duct obstruction . It is normal for the amount of semen to diminish with age.


The number of sperm in an ejaculation varies widely, depending on many factors including the time since the previous ejaculation, [ 18 ]  age, stress levels, [ 19 ]  and  testosterone . Longer time of sexual stimulation immediately preceding ejaculation can result in higher concentration of sperm. [ 17 ]  An unusually low sperm count, distinguished from low semen volume, is known as  oligospermia , and the absence of any sperm from the semen is termed  azoospermia .


The first ejaculation in males often occurs about 12 months after the onset of  puberty , generally through  masturbation  or  nocturnal emission  (wet dreams). This first  semen  volume is small. The typical ejaculation over the following three months produces less than 1 ml of semen. The semen produced during early puberty is also typically clear. After ejaculation this early semen remains jellylike and, unlike semen from mature males, fails to  liquefy . A summary of semen development is shown in Table 1.


Most first ejaculations (90%) lack sperm. Of the few early ejaculations that do contain sperm, the majority of sperm (97%) lack motion. The remaining sperm (3%) have abnormal motion. [ 20 ]


As the male proceeds through puberty, the semen develops mature characteristics with increasing quantities of normal sperm. Semen produced 12 to 14 months after the first ejaculation liquefies after a short period of time. Within 24 months of the first ejaculation, the semen volume and the quantity and characteristics of the sperm match that of adult male semen. [ 20 ]


^a  Ejaculate is jellylike and fails to liquefy.
 ^b  Most samples liquefy. Some remain jellylike.
 ^c  Ejaculate liquefies within an hour.


There is a  central pattern generator  in the  spinal cord , made up of groups of  spinal interneurons , that is involved in the rhythmic response of ejaculation. This is known as the  spinal generator for ejaculation . [ 21 ]


To map the neuronal activation of the brain during the ejaculatory response, researchers have studied the expression of  c-Fos , a  proto-oncogene  expressed in neurons in response to stimulation by hormones and neurotransmitters. [ 22 ]  Expression of c-Fos in the following areas has been observed: [ 23 ] [ 24 ]


Although uncommon, some men can achieve ejaculations during masturbation without any manual stimulation. Such men usually do it by tensing and flexing their abdominal and buttocks muscles along with vigorous fantasizing. Others may do it by relaxing the area around the  penis , which may result in harder erections especially when extremely aroused. [ 25 ]  Hands-free ejaculation can also be achieved by prostate stimulation alone, either  internally  (with the use of  sex toys , fingers or performing  anal sex  or  pegging ) or externally (such as  perineum  massages), [ 26 ] [ 27 ]  although  prostate orgasms  without ejaculation (dry orgasms) are also possible. [ 28 ]


Perineum  pressing results in an ejaculation which is purposefully held back by pressing on either the perineum or the urethra to force the seminal fluid to remain inside. In such a scenario, the seminal fluid stays inside the body and goes to the  bladder . Some people do this to avoid making a mess by keeping all the semen inside. [ 29 ]  As a medical condition, it is called  retrograde ejaculation . [ 30 ]


For most men, no detrimental health effects have been determined from ejaculation itself or from frequent ejaculations, [ citation needed ]  though sexual activity in general can have health or psychological consequences. A small fraction of men have a disease called  postorgasmic illness syndrome  (POIS), which causes severe muscle pain throughout the body and other symptoms immediately following ejaculation. The symptoms last for up to a week. [ 31 ] [ 32 ] [ 33 ]  Some doctors speculate that the frequency of POIS "in the population may be greater than has been reported in the academic literature", [ 34 ]  and that many POIS sufferers are undiagnosed. [ 35 ]


It is not clear whether frequent ejaculation has any effect on the risk of  prostate cancer . [ 36 ] [ 37 ] [ 38 ]  Two large studies examining the issue were [ 39 ] [ 40 ] [ 41 ]  "Ejaculation Frequency and Subsequent Risk of Prostate Cancer" [ 42 ]  and "Sexual Factors and Prostate Cancer". [ 43 ]  These suggest that frequent ejaculation after puberty offers some reduction of the risk of prostate cancer. The US study involving 29,342 US men aged 46 to 81 years [ 42 ]  suggested that "high ejaculation frequency was related to decreased risk of total prostate cancer". [ 42 ]  An Australian study involving 1,079 men with prostate cancer and 1,259 healthy men found that "there is evidence that the more frequently men ejaculate between the ages of 20 and 50, the less likely they are to develop prostate cancer":


[T]he protective effect of ejaculation is greatest when men in their twenties ejaculated on average seven or more times a week. This group were one-third less likely to develop aggressive prostate cancer when compared with men who ejaculated less than three times a week at this age. [ 44 ]


In mammals and birds, multiple ejaculation is commonplace. [ 45 ] [ 46 ] [ clarification needed ]  During copulation, the two sides of a  short-beaked echidna 's penis are used sequentially. Alternating between the two sides allows for persistent stimulation to induce ejaculation without impeding the refractory period. [ 47 ]


In  stallions , ejaculation is accompanied by a motion of the tail known as "tail flagging". [ 48 ]  When a male  wolf  ejaculates, his final  pelvic thrust  may be slightly prolonged. [ 49 ]  A male  rhesus monkey  usually ejaculates less than 15 seconds after  sexual penetration . [ 50 ]  The first report and footage of  spontaneous ejaculation  in an aquatic mammal was recorded in a wild  Indo-Pacific bottlenose dolphin  near  Mikura Island , Japan, in 2012. [ 51 ]


In horses, sheep, and cattle, ejaculation occurs within a few seconds, but in  boars , it can last for five to thirty [ 52 ]  minutes. [ 53 ]  Ejaculation in boars is stimulated when the spiral-shaped penis interlocks with the female's cervix. [ 54 ]  A mature boar can produce 250–300 ml (8.8–10.6 imp fl oz; 8.5–10.1 US fl oz) of semen during one ejaculation. [ 53 ]  In llamas and alpacas, ejaculation occurs continuously during copulation. [ 55 ]


The semen of male dogs is ejaculated in three separate phases. [ 56 ]  The last phase of a male canine's ejaculation occurs during the  copulatory tie , and contains mostly prostatic fluid. [ 57 ]


Frequent urination , or  urinary frequency  (sometimes called  pollakiuria ), is the need to  urinate  more often than usual.  Diuretics  are medications that increase urinary frequency.  Nocturia  is the need of frequent urination at night. [ 1 ]  The most common cause of this condition for women and children is a  urinary tract infection . The most common cause of urinary frequency in older men is an  enlarged prostate . [ 2 ]


Frequent urination is strongly associated with frequent incidents of  urinary urgency , which is the sudden need to urinate.  It is often, though not necessarily, associated with  urinary incontinence  and  polyuria  (large total volume of urine). However, in other cases, urinary frequency involves only normal volumes of urine overall. [ 3 ]   [ citation needed ]


The normal number of times varies according to the age of the person. Among young children, urinating 8 to 14 times each day is typical. This decreases to 6–12 times per day for older children, and to 4–6 times per day among teenagers. [ 4 ]


The most common causes of frequent urination are: [ citation needed ]


Less common causes of frequent urination are: [ citation needed ]


Diagnosis of the underlying cause requires a careful and thorough evaluation. [ 9 ]


Treatment depends on the underlying cause or condition. [ 10 ]


Glans insufficiency syndrome , also known as  soft glans ,  cold glans , or  glans insufficiency , is a medical condition that affects male individuals. This condition is characterized by the persistent inability of the  glans penis  to achieve and maintain an  erect  or turgid state during  sexual arousal , remaining soft and cold. This condition can have an impact on a person's  sexual function , including decreased sensitivity, difficulty in  maintaining an erection , and overall quality of life. [ 2 ] [ 3 ]


This condition is typically diagnosed among individuals who have undergone  penile implant  surgery, and is often underdiagnosed in the general population due to its complexity and the lack of clear nomenclature.


Most commonly three distinct pathophysiologies have been hypothesized: [ 2 ]


The exact causes of soft glans syndrome remain complex and multifactorial, potentially involving issues related to blood flow, nervous system function, hormonal imbalances, medication side effects, or trauma.


Possible explanation of lack of glanular engorgement is that the pressure within the glans penis during an erection is consistently lower than that within the  corpora cavernosa . Glans engorgement does not typically occur in response to  intracavernous injections  of vasoactive agents, and it is frequently absent following the implantation of a penile prosthesis. [ 4 ]


Patients who have undergone urethroplasty and  penile implantation  may encounter the glans remaining soft and cold despite the expected response to sexual stimulation. [ 5 ]
It has been reported that from 4 to 60% of people who underwent anterior urethroplasty surgery had a glans insufficiency syndrome. [ 6 ]


Treatment options may include mechanical, pharmacologic, or surgical approaches. Surgical interventions may involve ligation of veins and closure of iatrogenic shunts, but their effectiveness remains a subject of limited research.


In people who had received penile implantation, the problem was addressed through a combination of penile implant revision and a glanular enhancement procedure, which improved the outcome by alleviating cold glans syndrome. The method included venous stripping procedure of the retrocoronal plexus, followed by ligation of the  dorsal deep vein  (DDV) and circumflex veins (CVs) at the penile hilum. [ 7 ]


In a 1990 study, a treatment approach was used to repair isolated glans insufficiency due to venous leakage. The diagnosis was established by observing the rapid drainage of a  contrast agent  through the deep dorsal vein while conducting  pharmacodynamic   ultrasonography . The treatment involved the  surgical resection  and  ligation  of a segment of the deep dorsal vein, a procedure that aimed to reduce pathologic venous outflow from the glans during erections. This treatment effectively restored normal glans tumescence. [ 8 ]


The  Gleason grading system  is used to help evaluate the  prognosis  of men with  prostate cancer  using samples from a  prostate biopsy . Together with other parameters, it is incorporated into a strategy of  prostate cancer staging  which predicts prognosis and helps guide therapy. A Gleason score is given to  prostate  cancer based upon its  microscopic  appearance. [ 1 ]


Cancers  with a higher Gleason score are more aggressive and have a worse prognosis. Pathological scores range from 2 to 10, with higher numbers indicating greater risks and higher mortality. The system is widely accepted and used for clinical decision making even as it is recognised that certain biomarkers, like ACP1 expression, might yield higher predictive value for future disease course. [ 2 ]


The  histopathologic diagnosis of prostate cancer  has implications for the possibility and methodology of Gleason scoring. [ 3 ]  For example, it is not recommended in signet-ring adenocarcinoma or urothelial carcinoma of the prostate, and the scoring should discount the foamy cytoplasms seen in foamy gland carcinoma. [ 3 ]


A total score is calculated based on how  cells look under a microscope , with the first half of the score based on the dominant, or most common cell morphology (scored 1 to 5), and the second half based on the non-dominant cell pattern with the highest grade (scored 1 to 5). These two numbers are then combined to produce a total score for the cancer.


Most often, a  urologist  or  radiologist  will remove a cylindrical sample ( biopsy ) of prostate tissue through the  rectum  (or, sometimes the  perineum ), using hollow needles, and biomedical scientists in a histology laboratory prepare microscope slides for  H&E staining  and  immunohistochemistry  for diagnosis by a pathologist. If the prostate is surgically removed, a  pathologist  will slice the prostate for a final examination. [ citation needed ]


A pathologist  microscopically  examines the biopsy specimen for certain "Gleason" patterns. These Gleason patterns are associated with the following features: [ citation needed ]


In the present form of the Gleason system, prostate cancer of Gleason patterns 1 and 2 are rarely seen. Gleason pattern 3 is by far the most common. [ citation needed ]


After analyzing the tissue samples, the pathologist then assigns a grade to the observed patterns of the tumor specimen. [ citation needed ]


The pathologist then sums the pattern-number of the primary and secondary grades to obtain the final Gleason score. If only two patterns are seen, the first number of the score is that of the  tumor's  primary grade while the second number is that of the secondary grade, as described in the previous section. If three patterns are seen, the first number of the score would be the primary grade and the second number the pattern with the  highest  grade.


For example, if the primary tumor grade was 2 and the secondary tumor grade was 3 but some cells were found to be grade 4, the Gleason score would be 2+4=6. This is a slight change from the pre-2005 Gleason system where the second number was the secondary grade (i.e., the grade of the second-most common cell line pattern). [ 4 ]


Key- blue: Gleason pattern 3 region, yellow: Gleason pattern 4 region, red: Gleason pattern 5 region


Gleason scores range from 2 to 10, with 2 representing the most well-differentiated tumors and 10 the least-differentiated tumors. Gleason scores have often been categorized into groups that show similar biologic behavior: low-grade (well-differentiated), intermediate-grade, moderate to poorly differentiated or high-grade. [ 5 ]


More recently, an investigation of the Johns Hopkins Radical Prostatectomy Database (1982-2011) led to the proposed reporting of Gleason grades and  prognostic  grade groups as:


Prostate cancers with a Gleason score ≤ 6 usually have rather good prognoses.


The Gleason grade of architectural pattern is sometimes referred to as the Gleason architectural pattern. [ citation needed ]


The Gleason grade is based on tissue architectural patterns rather than purely cytological changes. These tissue patterns are classified into 5 grades, numbered 1 though 5. Lower numbers indicate more differentiation, with pattern 5 being the least differentiated. [ 4 ] [ 7 ]  Differentiation is the degree to which the tissue, in this case the tumor, resembles native tissue. Greater resemblance (lower grade) is typically associated with a better prognosis. [ citation needed ]


However, the Gleason score is not simply the highest grade (least differentiated) pattern within the tumor. Rather, it is a combination of the most two most frequent patterns seen. This recognizes that prostatic carcinomas have multiple patterns and that prognosis is more accurately determined by adding the scores of the two most prevalent patterns. Using this system, the grades of the most prevalent and second most prevalent patterns (if at least 5% of the total), are added together to yield the overall Gleason score. [ 4 ] [ 7 ]


For example, if the most prevalent pattern/grade is 2, and the second most prevalent grade is 1, then the Gleason score is 2+1=3. If the neoplasm has only one pattern, the grade of that pattern is doubled to obtain the score. For example, if a tumor is entirely grade 1, the Gleason score would be 1+1=2. The most differentiated tumor would have the lowest score, Gleason 2 (1+1), while the most undifferentiated neoplasm (not resembling native prostate tissue) would have the highest score, Gleason 10 (5+5). Gleason scores range from 2 to 10; by definition there is no score of 0 or 1. [ 4 ] [ 7 ]


Cytological differences between normal prostate and neoplastic glands are evident in changes to the typical two cell layers of the gland. In prostatic adenocarcinoma, the basal (bottom, usually cuboidal type) cell layer is lost, with only the top layer (usually columnar to pseudostratified) remaining. [ citation needed ]


Using this system, the most well-differentiated tumors have a Gleason score/grade of 2, and the least-differentiated tumors a score of 10. Range by definition is from 2-10, with architectural type from 1-5, and always added together or doubled, as described above. Gleason scores are often grouped together, based on similar behaviour: Grade 2-4 as well-differentiated, Grade 5-6 as intermediately-differentiated, Grade 7 as moderately to poorly differentiated (either 3+4=7, where the majority is pattern 3, or 4+3=7 in which pattern 4 dominates and indicates less differentiation., [ 6 ]  and Grade 8-10 as "high-grade." [ 4 ] [ 7 ]


Gleason pattern 1 is the most well-differentiated tumor pattern. It is a well-defined nodule of single/separate, closely/densely packed, back-to-back gland pattern that does not invade into adjacent healthy prostatic tissue. The glands are round to oval shaped and proportionally large, compared to Gleason pattern 3 tumors, and are approximately equal in size and shape to one another. [ 4 ] [ 7 ]


Gleason 2 is fairly well-circumscribed nodules of single, separate glands. However, the glands are looser in arrangement and not as uniform as in pattern 1. Minimal invasion by neoplastic glands into the surrounding healthy prostate tissue may be seen. Similar to Gleason 1, the glands are usually larger than those of Gleason 3 patterns, and are round to oval in shape. Thus the main difference between Gleason 1 and 2 is the density of packing of the glands seen; invasion is possible in Gleason 2, but by definition not in Gleason 1. [ 4 ] [ 7 ]


Gleason 3 is a clearly infiltrative neoplasm, with extension into adjacent healthy prostate tissue. The glands alternate in size and shape, and are often long/angular. They are usually small/micro-glandular in comparison to Gleason 1 or 2 grades. However, some may be medium to large in size. The small glands of Gleason 3, in comparison to the small and poorly defined glands of pattern 4, are distinct glandular units. Mentally you could draw a circle around each of the glandular units in Gleason 3. [ 4 ] [ 7 ]


Gleason pattern 4 glands are no longer single/separated glands like those seen in patterns 1-3. They look fused together, difficult to distinguish, with rare lumen formation vs Gleason 1-3 which usually all have open lumens (spaces) within the glands, or can be cribriform-(resembling the cribriform plate/similar to a sieve: an item with many perforations). Fused glands are chains, nests, or groups of glands that are no longer entirely separated by stroma-(connective tissue that normally separates individual glands in this case). Fused glands contain occasional stroma giving the appearance of "partial" separation of the glands. Due to this partial separation, fused glands sometimes have a scalloped (think looking at a slice of bread with bite taken out of it) appearance at their edges. [ 4 ] [ 7 ]


Neoplasms have no glandular differentiation (thus not resembling normal prostate tissue at all). It is composed of sheets (groups of cells almost planar in appearance (like the top of a box), solid cords (group of cells in a rope like fashion running through other tissue/cell patterns seen), or individual cells. You should not see round glands with lumenal spaces that can be seen in the other types that resemble more the normal prostate gland appearance. [ 4 ] [ 7 ]


Gleason scores 2-4 are typically found in smaller tumors located in the transitional zone (around the urethra). These are typically found incidentally on surgery for benign prostatic hyperplasia, which is not itself a precursor lesion for prostatic carcinoma. [ 4 ]


The majority of treatable/treated cancers are of Gleason scores 5-7 and are detected due to biopsy after abnormal  digital rectal exam  or  prostate specific antigen  evaluation.  The cancer is typically located in the peripheral zone usually the posterior portion, explaining the rationale of performing the digital rectal exam. [ citation needed ]


Tumors with Gleason scores 8-10 tend to be advanced neoplasms that are unlikely to be cured. Although some evidence suggests that prostate cancers will become more aggressive over time, Gleason scores typically remain stable for several years. [ 4 ]


The Gleason scores then become part of the TNM or Whitmore-Jewett  prostate cancer staging  system to provide prognosis.


The Gleason scoring system takes its name from  Donald Gleason , a pathologist at the Minneapolis Veterans Affairs Hospital, who developed it with colleagues at that facility in the 1960s. [ 8 ] [ 9 ]
In 2005 the International Society of Urological Pathology altered the Gleason system, refining the criteria and changing the attribution of certain patterns. [ 4 ]  It has been shown that this "modified Gleason score" has higher performance than the original one, and is currently assumed standard in urological pathology. In this form, it remains an important tool. [ 10 ]


However, problematic aspects of the original Gleason grading system still characterize the 2005 revision. The predominant lowest score assigned is Gleason 3+3 = 6. Patients who are told their Gleason score is 6 out of 10 may interpret that they have a more aggressive intermediate cancer and experience greater  anxiety . [ 11 ]  More importantly, some classification systems fail to clearly distinguish between Gleason 3+4 = 7 and Gleason 4+3 = 7, with the latter having a worse prognosis.


Therefore, in 2014 an international multidisciplinary conference was convened to revise the 2005 system. A 5-point Gleason Grade grouping similar to those such as  PI-RADS  used with prostate MRI evaluations was proposed to denote prognostically distinct stratification. Grade 1 would indicate the lowest-risk cancer while Grade 5 would indicate the most aggressive disease. The system was tested and validated against 20,000 prostatectomy specimens and at least 16,000 biopsy samples.


The majority of conference participants concurred on the superiority of the scale over the 2005 Gleason grading system, pointing to the likelihood that  overtreatment  could be avoided for those patients whose cancer was assigned Grade 1. The  World Health Organization 's 2016 edition of  Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs  has accepted the 2014 system, which can be used in conjunction with the 2005 Gleason system. [ 12 ]


The  Gold Cystoscope Award  founded in 1936, revised in 1977, and named after the  cystoscope , is awarded annually by the  American Urological Association . The first recipient was Donald G. Skinner. [ 1 ] [ 2 ]


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


This  award -related article is a  stub . You can help Wikipedia by  expanding it .


Dr.  Mohan S. Gundeti  is an Indian pediatric urological surgeon and professor of surgery. Gundeti has served as the Chief of Pediatric Urology at the  University of Chicago  Comer Children’s Hospital in Chicago, Illinois since 2007.


Prior to his appointment at The University of Chicago, Gundeti was a locum consultant in pediatric urological surgery at the  Great Ormond Street Hospital for Children  and  Guy’s and St. Thomas’ Hospital  in London, where he worked and trained from 1999 to 2005.


At The University of Chicago, in 2008, Gundeti (as team leader) performed the world’s first robot-assisted bladder reconstructive surgery. [ 1 ]  for a pediatric patient.


Gundeti has co-authored and edited several textbooks and publications, including the “Robotic Urological Surgery” Textbook [ 2 ]  published in 2022.


Gundeti has developed multiple robotic surgical techniques for pediatric urology. The first is The University of Chicago RALIMA (Robot Assisted Laparoscopic Bladder Augmentation Ileocystoplasty with Mitrofanoff Appendicovesicostomy) Technique. [ 3 ] [ 4 ]


In 2011, Gundeti began developing the  LUAA "Gundeti" Technique  for surgical correction of vesicoureteral reflux. [ 5 ] [ 6 ]


Gundeti’s research in clinical outcomes of complex urological surgery have been recognized by the  American Urological Association (AUA)  and  European Society of Pediatric Urology (ESPU) . He is now researching applications of Machine Learning to aid in diagnosing kidney diseases through funding from the  Chicago Institute for Translational Medicine (ITM)  Pilot Awards Program along with  Maryellen Giger.


Gundeti is the author and editor of the educational textbooks “Blackwell Wiley Pediatric Robotic and Reconstructive Urology: A Comprehensive Guide” [ 7 ]  published in 2012, and “Surgical Techniques in Pediatric and Adolescent Urology", [ 8 ]  published in 2020. Gundeti was also the co-editor and co-author of the "Robotic Urological Surgery" [ 9 ]  textbook which was published in 2022.


He co-edited and authored an online textbook, the "Pediatric Urology Book" [ 10 ]  in order to reduce restrictions to access, which was published in 2023. In addition to these major publications, Gundeti has co-authored over 200 publications, [ 11 ] [ 12 ]  including book chapters, peer-reviewed journal articles, and review articles.


Between the years of 2013 and 2021, Gundeti was the Consulting Editor of  the British Journal of Urology International (BJUI) , and is presently an Associate Editor of the Urology Video Journal [ 13 ]  and JU Open Plus. [ 14 ]


2012: Third Prize Basis Research Award for Clinical Research study entitled “Is Pelvic Plexus Nerve Identification possible during the Robotic Assisted Laparoscopic Ureteric Reimplantation (RALUR)” [ 15 ]  awarded by the European Society of Pediatric Urology (ESPU).


2014: Recognized as one of America’s Top Doctors and Best Doctor in Chicago by Castle Connolly [ 16 ]


2016: Hans Marberger Award [ 17 ]  awarded by the  European Association of Urology  (EAU).


The  International Prostate Symptom Score (IPSS)  is an eight-question written  screening  tool used to screen for, rapidly diagnose, track the symptoms of, and suggest management of the  lower urinary tract symptoms  of  benign prostatic hyperplasia  (BPH).


It contains seven questions related to symptoms related to BPH and one question related to the patient's perceived  quality of life . Created in 1992 by the  American Urological Association , it originally lacked the eighth quality of life question, hence its original name: the American Urological Association symptom score (AUA-7). [ 1 ]  World Health Organization International Consultation on BPH adopted the "eight question" index and labeled it the IPSS. [ 2 ]


The seven questions relating to symptoms experienced in the last month include  feeling of incomplete bladder emptying ,  frequency of urination ,  intermittency of urine stream ,  urgency of urination , weak stream, straining and  waking at night to urinate . [ 1 ]


The IPSS was designed to be self-administered by the patient, with speed and ease in mind. Hence, it can be used in both urology clinics as well as the clinics of primary care physicians (i.e. by general practitioners) for the screening and diagnosis of BPH. [ 1 ]


Additionally, the IPSS can be performed multiple times to compare the progression of symptoms and their severity over months and years. [ 1 ]


In addition to diagnosis and charting disease progression, the IPSS is effective in helping to determine treatment for patients. [ 1 ]


The symptoms must have been experienced in the last month and each answer is scored from 0 to 5 for a maximum score of 35 points. [ 1 ]


The first six questions are scored based on the following: [ 1 ]


The seventh question, relating to nocturia, is scored from 0 to 5 based on how many times the patient gets up at night to urinate (viz. 1 is scored for one time per night and 5 for five times per night). [ 1 ]


The eighth, and final question (not included in the main IPSS score), relating to the patient's perceived  quality of life , is assigned a score of 0 (delighted) to 6 (terrible). [ 3 ]


The  mnemonic  "FUN WISE" can be used to remember the seven questions relating to symptoms of BPH. They are as follows:


In research, the IPSS is used to standardise patients' complaints and symptoms. However, a meta-analysis on the subject of the influence of position (whether standing or sitting) on  urodynamics  (that is, on tests of how completely the bladder, sphincter and urethra store and release urine) noted that, in most cases, physicians either did not use the IPSS, or did not use it adequately. [ 4 ]


Intravesical drug delivery  is the  delivery of medications  directly into the  bladder  by  urinary catheter . This method of drug delivery is used to directly target diseases of the bladder such as  interstitial cystitis  and  bladder cancer , but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of  permeability enhancers , advances in intravesical  drug carriers , and  mucoadhesive , intravesical drug delivery is becoming more effective and of increased interest in the medical community.


Delivering drugs directly to the target bladder site allows for maximizing drug delivery while minimizing  systemic effects .
Delivering the treatment directly to the site allows for more effective dosages to be given since high concentrations of drug in the bladder can be reached. [ 1 ]  This becomes especially important when patients have a  urinary bladder disease  that is  drug resistant . The delivery of drugs directly to the bladder is a large improvement over systemic delivery which only allows a small fraction of the drug to reach the bladder, causing lower concentrations of drug leading to systemic treatments being ineffective. [ 1 ]  The smaller fraction of drug reaching its target with systemic delivery means more drugs must be administered which can lead to problems with systemic  toxicity . This is not the case when drug is administered directly to the bladder.


The layer of the bladder which comes into contact with urine, the urothelium (the  transitional epithelium  of the bladder, is a mostly impermeable barrier which stops molecules in the urine from being reabsorbed and prevents molecules from being secreted directly into the bladder as well. [ 1 ]   The bladder’s impermeability means that any drug delivered intravesical will not absorb into the bloodstream well through the bladder wall, causing fewer systemic effects. This impermeability also causes treatment of bladder diseases to be more difficult to treat as drugs do not absorb well into the bladder wall. Intravesical drug delivery has been identified as an ideal way to treat most urinary disorders, including bladder tumors and  bladder cancers ,  interstitial cystitis , and  urinary incontinence . [ 1 ] [ 2 ]
 [ 3 ] [ 4 ] [ 5 ]  There is currently a lack of interest in treating  urinary tract infections  using intravesical delivery.


While intravesical delivery shows distinct advantages over systemic drug delivery it has several problems to overcome. When giving a drug intravesically it is  diluted  by urine and washed out when urine is voided. [ 1 ] [ 2 ] [ 3 ]  Additionally, the low permeability of the urothelium which lines the bladder creates a hurdle that must be overcome if the bladder wall needs to be treated. [ 3 ]  These issues create the need for more frequent dosing, which causes urinary catheter site irritation and compliance issues with treatments. [ 2 ]
Intravesical drug dilution occurs as urine accumulates in the bladder, lowering the concentration of drug in the bladder as overall volume increases. The  voiding  of drug with urine when using traditional drug formulations in the bladder has become a hurdle to overcome as well, since  residence time  of the drug inside the bladder is directly tied to the treatment’s  efficacy . [ 1 ]  Creating  formulations  which adhere to the bladder wall has been targeted as one way to improve intravesical dug efficacy,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The low adherence of drugs to the bladder wall and low permeability into the bladder wall contributes to low drug retention in the bladder. [ 1 ]  When modifying drug formulations for intravesical delivery gels or  viscosity  increasing formulations are sometimes used to increase retention, though this can cause issues with  urethra obstruction , an additional hurdle in intravesical drug delivery. [ 2 ]
Permeability issues with the bladder wall can be attributed to the urothelium, the lining of the bladder wall made up of  umbrella cells , intermediate cells, and basal cells.,. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The impermeability can be attributed to the umbrella cells which form tight junctions with each other to make up the innermost layer of the urothelium and have the ability to change shape to adapt to the bladder’s varying size. [ 1 ] [ 2 ]  The umbrella cells are covered in a dense layer of plaques which further prevents the absorption of particles through the urothelium and a layer of  mucin  composed of  glycosaminoglycans  (GAGs) which prevents both hydrophobic and negatively charged molecules from adhering to the bladder wall. [ 1 ] [ 4 ]  Overcoming the impermeability of the mucin layer and the urothelium is a large focus of many intravesical drug formulations, and is key to an efficacious intravesical treatment [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


The main ways researchers are currently overcoming the problems in intravesical drug delivery are through developing formulations using  mucoadhesives ,  nanoparticles ,  liposomes , polymeric  hydrogel , expandable delivery devices, and electromotive drug administration. [ 1 ] [ 2 ] [ 3 ]  These methods each serve to improve retention time, drug permeability through the urothelium, or some combination of the two.


Enhancing Drug retention can be achieved through changing formulation and delivery device. Often drug retention and permeability enhancement are tied, as drugs which permeate the urothelium will suffer fewer effects from urine dilution and voiding. Two of the most common methods to improve drug retention are by using a  mucoadhesive  formulation or using polymeric  hydrogels  that form in the bladder, or  in situ  gelling hydrogels. [ 1 ] [ 2 ] [ 3 ]


Mucoadhesive formulations can be made with both  biopolymers  and  synthetic polymers , and usually contain polymers that are  hydrophilic  and can form many  hydrogen bonds  with the  GAG-mucin . [ 1 ]  Positively charged molecules typically make far better mucoadhesive as the mucin layer is negatively charged. [ 6 ]  By forming these bonds, the mucoadhesive, and the drug it carries, can maintain sustained contact with the bladder wall, enhancing retention of the drug in the bladder. Among mucoadhesive materials  Chitosan  often stands out due to its  biocompatibility ,  biodegradability , and permeability enhancing factors. [ 3 ]  In experiments with chitosan, it has been shown that the mucoadhesive properties of a molecule likely increase as the  molecular weight  is increased. [ 7 ]  Studies have also found that the modification of chitosan formulations with  thiomers , which can form covalent bonds with mucus, can significantly improve the mucoadhesion of the chitosan formulations [ 8 ]


Polymeric  hydrogels  for intravesical drug delivery take advantage of characteristics of the bladder or urine to gel, or may use external manipulation to cause the hydrogel to form. [ 1 ] [ 9 ]  These gels can take advantage of pH or temperature differences, or external input like  UV  lasers, to form gels inside the bladder after instillation of the formulation in liquid form. [ 9 ]  If these gels are made to be mucoadhesive they stick to the bladder wall and do not wash out or cause urethral obstruction. Polymeric hydrogels have also been formulated to float on top of the urine to avoid wash out and obstruction without having to adhere to the bladder wall. [ 10 ]  Drawbacks of using polymeric hydrogel formulations include the concern of urethral obstruction, the varying conditions of the urine which make pH or ionic controlled gelling formulations less controlled, and the  bladder wall inflammation  which can occur with mucoadhesive polymeric hydrogels. [ 2 ]


Enhancing drug permeability can be done through physical or chemical methods, and is also achieved through  nanoparticle  and  liposome   drug carriers . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  Physical methods include electromotive drug administration, radiofrequency-induced chemotherapeutic effect, and conductive hyperthermic  chemotherapy , but electromotive drug administration seems to be the most prevalent in recent research and clinical trial focus. [ 1 ] [ 2 ] [ 3 ] [ 5 ] [ 11 ]  Chemical methods revolve around adding a chemical agent to enhance drug uptake and increase permeability. To enhance drug permeability through physical or chemical methods both the  mucin layer  and the  umbrella cells  of the urothelium must undergo a structural or chemical change. [ 1 ]


Electromotive drug administration utilizes a small  electric current  flowing across the bladder wall between two  electrodes , one on the skin and one placed inside the bladder via  catheterization , to enhance permeability of  aqueous  solutions. [ 1 ] [ 2 ] [ 3 ]  Electromotive drug administration best enhances  ionized  formulations, which diffuse poorly using standard  passive diffusion . [ 3 ]  This allows it to potentially assist in the delivery of many drugs that usually perform poorly in the bladder without having to change their formulations heavily. Across multiple studies and clinical trials electromotive drug administration has been shown to increase the uptake of many drugs, showing potential use in  bladder cancer ,  urinary incontinence ,  urinary cystitis  and pain management. [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Cost of  local anesthesia  for bladder distention using electromotive drug administration in combination with  lidocaine  has been shown to be cheaper and more practical than  general anesthesia  or  spinal anesthesia . [ 5 ]


To enhance the permeability of the bladder wall, specifically the urothelium, to drugs administered locally to the bladder four chemical agents are most commonly used:  DMSO ,  protamine sulphate ,  Hyaluronidase , and  chitosan . DMSO is already widely used to directly treat urinary cystitis due to its  anti-inflammatory  and  antibacterial  properties. [ 1 ] [ 3 ]  DMSO can penetrate tissues without causing any damage to them. [ 1 ] [ 3 ]  This property of DMSO made it of particular interest as a chemical enhancer and it has been shown to increase the uptake of several chemotherapeutics used intravesically. [ 12 ]  Protamine sulphate causes disruption to the mucus layer of the urothelium and can cause large disruption of bladder permeability which can be modified by adding  defibrotide . [ 1 ] [ 3 ]  Hyaluronidase breaks down  Hyaluronic acid , a GAG molecule important to the  mucin layer , causing enhanced permeability of the mucin layer to drugs administered concurrently with hyaluronidase. [ 1 ]  Conversely, hyaluronic acid can be used to treat  interstitial cystitis  as it helps to repair damaged mucin layers. [ 3 ]  Chitosan is thought to function as a permeability enhancer by binding to the mucin layer and negatively affecting tight junctions between  umbrella cells  in the urothelium. [ 1 ]  It has been shown that chitosan increases bladder wall permeability but its effectiveness as a permeability enhancer decreases as calcium ion concentration increases. [ 13 ]  Chemically enhancing bladder permeability can lead to negative side effects such as  incontinence , pain, and uncontrolled leakage of molecules other than intended drug from the urine into the bladder wall. [ 1 ]


Nanoparticle  and  liposome   drug carrier  formulations allow for increased drug uptake, especially in the case of liposomes which allow for greater uptake via  endocytosis . [ 1 ] [ 2 ] [ 3 ] [ 5 ]  Liposomes generally must be shielded via modification with a  Polyethylene glycol  molecule to overcome issues with instability and  aggregation  in urine. [ 4 ]  Nanoparticle and Liposome drug carriers can be loaded into a  in situ  forming hydrogel to gain the advantages of mucoadhesive properties [ 4 ]  Empty liposomes by themselves have been noted to improve interstitial cystitis, most likely due to formation of a lipid film on damaged urothelium. [ 3 ] [ 5 ]  The variety of types of nanoparticles which can be made to carry drugs in intravesical formulations, combined with the tunability of many of these particles in regards to drug loading and release rates makes nanoparticles and liposomes a highly versatile and useful tool in intravesical drug delivery. [ 1 ]


This is a  list of recipients of the  St Peter's Medal , the highest award of the  British Association of Urological Surgeons  (BAUS). [ 1 ]


The  maiden waist deformity  is a  radiologic sign  associated with  retroperitoneal fibrosis , a condition resulting from the abnormal proliferation of fibrous tissue in the  retroperitoneal space . The fibrosis can extend to adjacent anatomical structures, frequently encompassing and obstructing the  ureters . [ 1 ]  This sign refers to the alteration in the normal course of the ureters: when the fibrosis causes both ureters to be pulled medially, they may form the appearance of a "narrow-waisted maiden". [ 2 ]


Male contraceptives , also known as  male birth control , are methods of preventing  pregnancy  by interrupting the function of sperm. [ 1 ]  The main forms of male  contraception  available today are  condoms ,  vasectomy , and  withdrawal , which together represented 20% of global contraceptive use in 2019. [ 2 ] [ 3 ] [ 4 ] [ 5 ]   New forms of male contraception are in  clinical  and  preclinical  stages of  research and development , but as of 2024, none have reached  regulatory approval  for widespread use. [ 6 ] [ 7 ] [ 8 ] [ 9 ]


These new methods include topical creams, daily pills, injections, long-acting implants, and external devices, and these products have both hormonal and non-hormonal mechanisms of action. [ 6 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ]   Some of these new contraceptives could even be  unisex , or usable by any person, because they could theoretically incapacitate mature sperm in the man's body before  ejaculation , or incapacitate sperm in the body of a woman after  insemination . [ 16 ] [ 17 ]


In the 21st century, surveys indicated that around half of men in countries across the world have been interested in using a variety of novel contraceptive methods, [ 18 ] [ 19 ] [ 20 ] [ 21 ]  and men in clinical trials for male contraceptives have reported high levels of satisfaction with the products. [ 12 ] [ 22 ]   Women worldwide have also shown a high level of interest in new male contraceptives, and though both male and female partners could use their own contraceptives simultaneously, women in long-term relationships have indicated a high degree of trust in their male partner's ability to successfully manage contraceptive use. [ 18 ] [ 23 ] [ 24 ]


A modelling study from 2018 suggested that even partial adoption of new male contraceptives would significantly reduce  unintended pregnancy  rates around the globe, [ 25 ]  which remain at nearly 50%, even in developed countries where women have access to modern contraceptives. [ 26 ] [ 27 ] [ 28 ]   Unintended pregnancies  are associated with negative socioeconomic, educational, and health outcomes for women, men, and the resulting children (especially in historically marginalized communities), [ 27 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ]  and 60% of unintended pregnancies end in  abortions , [ 35 ] [ 36 ]  many of which are  unsafe  and can lead to women's harm or death. [ 37 ] [ 38 ] [ 39 ] [ 40 ]   Therefore, the development of new male contraceptives has the potential to improve racial, economic, and gender equality across the world, advance  reproductive justice  and  reproductive autonomy  for all people, and save lives.


Vasectomy is surgical procedure for permanent male  sterilization  usually performed in a physician's office in an outpatient procedure. [ 41 ]  During the procedure, the  vasa deferentia  of a patient are severed, and then tied or sealed to prevent sperm from being released during ejaculation. [ 42 ]  Vasectomy is an effective procedure, with less than 0.15% of partners becoming pregnant within the first 12 months after the procedure. [ 43 ]  Vasectomy is also a widely reliable and safe method of contraception, and complications are both rare and minor. [ 44 ] [ 45 ]   Vasectomies can be reversed, though rates of  successful reversal  decline as the time since vasectomy increases, and the procedure is technically difficult and often costly. [ 42 ] [ 46 ] [ 41 ]


A condom is a  barrier device  made of  latex  or thin plastic film that is rolled onto an erect  penis  before intercourse and retains ejaculated  semen , thereby preventing pregnancy. [ 47 ]  Condoms are less effective at preventing pregnancy than vasectomy or modern methods of female contraception, with a real-world failure rate of 13%. [ 43 ]  However, condoms have the advantage of providing protection against some  sexually transmitted infections  such as  HIV/AIDS . [ 48 ] [ 49 ]  Condoms may be combined with other forms of contraception (such as  spermicide ) for greater protection. [ 50 ]


The withdrawal method, also known as  coitus interruptus  or pulling out, is a behavior that involves halting penile-vaginal intercourse to remove the penis out and away from the  vagina  prior to ejaculation. [ 51 ] [ 52 ]  Withdrawal is considered a less-effective contraceptive method, with typical-use failure rates around 20%. [ 41 ] [ 43 ]  However, it requires no equipment or medical procedures. [ 51 ]


Researchers have been working to generate novel male contraceptives with diverse mechanisms of action and possible delivery methods, including  long-acting reversible contraceptives  (LARCs), daily  transdermal gels , daily and on-demand oral pills, monthly  injectables , and  implants. [ 53 ] [ 54 ] [ 55 ]  Efforts to develop male contraceptives have been ongoing for many decades, but progress has been slowed by a lack of funding and industry involvement. As of 2024, most funding for male contraceptive research is derived from government or philanthropic sources. [ 56 ] [ 57 ] [ 58 ] [ 59 ]


Novel male contraceptives could work by blocking various steps of the  sperm development process , blocking sperm release, or interfering with any of the sperm functions necessary to reach and fertilize an egg in the female reproductive tract. [ 60 ]   Advantages and disadvantages of each of these approaches will be discussed below, along with relevant examples of products in development.


These methods work by preventing the testes from producing sperm, or interfering with sperm production in a way that leads to the production of nonfunctional sperm. [ 61 ]   This approach can be accomplished by either  hormonal  or nonhormonal small-molecule drugs, or potentially by thermal methods.  The effectiveness of contraceptives in this group can be easily assessed microscopically, by measuring sperm count or abnormalities in sperm shape, but because  spermatogenesis  takes approximately 70 days to complete, [ 62 ]  these methods are likely to require approximately three months of use before they become effective, and approaches that halt sperm production at an early stage of the process may result in reduced testicular size. [ 63 ]  Methods have been suggested in the 1980s. [ 64 ]


Hormonal contraceptives for men work similarly to  hormonal female methods , using  steroids  to interrupt the  hypothalamic-pituitary-gonadal axis  and thereby block sperm production. Administering external  androgens  and  progestogens  suppresses secretion of the  gonadotropins   LH  and  FSH , which impairs  testosterone  production and sperm generation in the testes, leading to reduced sperm counts in ejaculates within 4–12 weeks of use. [ 65 ]  However, since the contraceptives contain testosterone or related androgens, the levels of androgens in the blood remain relatively constant, thereby limiting side effects and maintaining masculine  secondary sex characteristics  like muscle mass and hair growth. [ 65 ]


Multiple methods of male hormonal contraception have been tested in  clinical trials  since the 1990s, and although one trial was halted early, leading to a large amount of press attention, [ 66 ] [ 67 ] [ 68 ] [ 69 ] [ 70 ]  most hormonal male contraceptives have been found to be effective, reversible, and well-tolerated. [ 71 ] [ 72 ] [ 73 ] [ 74 ] [ 75 ] [ 76 ]


As of 2024 [update] , the following hormonal male contraceptive products are in clinical trials:


Some anabolic steroids may exhibit suppressive effects on spermatogenesis, but none are being investigated for use as a male contraceptive. [ 84 ]


Non-hormonal contraceptives for men are a diverse group of molecules that act by inhibiting any of the many  proteins  involved in sperm production, release, or function.  Because sperm cells are highly specialized, they express many proteins that are rare in the rest of the human body. [ 85 ] [ 86 ] [ 87 ]   This suggests the possibility that non-hormonal contraceptives that specifically block these sperm proteins could have fewer side effects than hormonal contraceptives, since sex steroid receptors are found in tissues throughout the body. [ 88 ]   Non-hormonal contraceptives can work by blocking spermatogenesis, sperm release, or mature sperm function, resulting in products with a wide variety of usage patterns, from slow onset to on-demand usage. [ 89 ]   Contraceptives targeting mature sperm functions could even be taken by both sperm-producing and egg producing people. [ 17 ] [ 16 ]   Challenges of non-hormonal contraceptive development include  bioavailability  and delivery past the  blood-testis barrier . [ 90 ]


As of 2024 [update] , the following non-hormonal male contraceptive product is in clinical trials:


As of 2024 [update] , the following non-hormonal male contraceptive products are in  preclinical development :


Prolonged testicular heating had been shown to reduce sperm counts in 1941, [ 115 ]  considered as a method of birth control after 1968 and in the 1980s [ 116 ] [ 117 ]  No modern clinical trials have demonstrated the safety, contraceptive effectiveness, or reversibility of this approach. Various devices are in early preclinical stages of development, and as of 2017 some approaches have been used by men through  self-experimentation . [ 14 ] [ 118 ]   As of 2015, the mechanism by which heating disrupts spermatogenesis was still not fully understood. [ 119 ]  There have been theoretical  concerns that prolonged heating could increase the risk of  testicular cancer  since the inborn birth defect of  cryptorchidism  carries a risk of testicular cancer [ 120 ]  or that heating could damage sperm DNA, resulting in harm to potential offspring. [ 121 ]


These approaches work by either physically or chemically preventing the emission of sperm during ejaculation, and are likely to be effective on-demand.


α1-adrenoceptor antagonists  and  P2X1  antagonists have been shown to inhibit  smooth muscle  contractions in the  vas deferens  during ejaculation, and therefore prevent the release of semen and sperm while maintaining the sensation of  orgasm . [ 122 ] [ 123 ] [ 124 ]  Various molecules in these categories are under consideration as possible on-demand male contraceptives.


Vas-occlusive contraception  is a form of male  contraception  that blocks  sperm  transport in the  vas deferens , the tubes that carry sperm from the  epididymis  to the  ejaculatory ducts .


Vas-occlusive contraception  provides a contraceptive effect through physical blockage of the  vas deferens , the  duct  connecting the  epididymis  to the  urethra . While a  vasectomy  excises, or removes, a piece of each vas deferens and occludes the remaining open ends of the duct, vas-occlusive methods aim to block the duct while leaving it intact.  Vas-occlusive methods generally aim to create  long-acting reversible  options, through a second procedure that removes the blockage. [ 138 ]   However, full reversibility remains questionable, since animal and human studies have shown sperm abnormalities, incomplete recovery of sperm parameters, and the development of fertility-impairing  antibodies  against one's own sperm after blockage removal. [ 111 ] [ 139 ] [ 140 ] [ 141 ] [ 142 ] [ 143 ]


As of 2024 [update] , the following vas-occlusive male contraceptive products are in clinical trials:


As of 2024 [update] , the following vas-occlusive male contraceptive products are in preclinical development:


Research into new, more acceptable designs of condoms is ongoing. [ 164 ] [ 165 ]


These approaches work by blocking functions that mature sperm need in order to reach and fertilize an egg in the female reproductive tract, such as  motility ,  capacitation , semen liquification, or  fertilization .  Drugs or devices that target mature sperm are likely to be effective on-demand (taken just before intercourse), and could even be delivered either in sperm-producing or egg-producing bodies, leading to unisex contraceptives. [ 17 ] [ 16 ]


As of 2024 [update] , the following non-hormonal male contraceptive approaches are in  preclinical  or early development:


Although some people question whether men would be interested in managing their own contraceptives [ 188 ]  or whether women would trust their male partners to do so successfully, [ 189 ]  studies consistently show that men around the world have significant levels of interest in novel forms of male contraception [ 18 ] [ 23 ] [ 190 ] [ 19 ] [ 191 ] [ 192 ]  and that women in committed relationships would generally trust their male partners to manage the contraceptive burden in the relationship. [ 23 ]   Additionally, males participating in various contraceptive clinical trials have reported high satisfaction with the products they were using. [ 81 ] [ 12 ] [ 22 ]


Studies on potential uptake indicate that in most countries, more than half of men surveyed would be willing to use a new method of male contraception. [ 18 ] [ 20 ] [ 190 ] [ 193 ] [ 194 ] [ 195 ]   Interestingly, some of the highest rates were reported in low-income countries like Nigeria and Bangladesh where 76% of men surveyed indicated that they would be willing to use a new method within the first 12 months that it is available. [ 18 ]  This is particularly compelling, since it has been estimated that a mere 10% uptake of new male contraceptive methods could avert nearly 40% of unintended pregnancies in Nigeria. [ 25 ]   Across the world, many young and middle-aged men especially want the ability to control their own fertility, and are not well-served by existing family planning programs. [ 196 ]


Although a phase II trial for an injectable male contraceptive was halted in 2011 by an independent data safety monitoring board due likely to rare adverse effects experienced by some participants, [ 197 ] [ 67 ]  leading many popular articles to suggest men could not tolerate side effects similar to those that many women endure on hormonal birth control, [ 70 ] [ 198 ]  in reality more than 80% of the study's male participants stated at the end of the trial that they were satisfied with the contraceptive injection, and would be willing to use the method if it were available. [ 199 ]   Subsequent hormonal male contraceptive clinical trials have progressed successfully, showing high levels of efficacy and acceptability among the participants. [ 12 ] [ 22 ] [ 81 ] [ 200 ]


It is sometimes assumed that women won’t trust men to take contraceptives, since women would bear the consequences of a male partner's missed dose or misuse. [ 189 ]   Of course, male contraceptive options would not have to replace female contraceptives, and in casual sexual encounters both partners may prefer to independently control their own contraceptive methods.  On the other hand, some long-term couples might want only one partner to bear the contraceptive burden. Indeed, there is evidence that a large proportion of women in relationships in many countries around the world would trust their partners to take a potential male method, [ 24 ] [ 18 ]  and many women want more male partner involvement in their own reproductive health services. [ 201 ]   Further, current contraceptive use data show that more than a quarter of women worldwide already rely on male-controlled methods for contraception (such as condoms and vasectomy), [ 202 ]  and this figure could grow as more male contraceptive methods become available.


Despite the fact that modern female pharmaceutical contraception has been on the market since the 1960s, [ 203 ]  40-50% of pregnancies are still  unintended  worldwide, leading to an approximate total of 121 million  unintended pregnancies  annually. [ 204 ] [ 205 ] [ 206 ]   Importantly, most studies on unintended pregnancies only measure women's intentions about the pregnancy, and so pregnancies that were unintended by men are understudied and may be under-reported. [ 207 ]   Unintended pregnancies have been shown to be linked with a wide variety of negative outcomes on mental and physical health, as well as educational and socioeconomic attainment in both parents and the children born of unintended pregnancies. [ 27 ] [ 29 ] [ 30 ] [ 32 ] [ 33 ] [ 34 ]


Surprisingly, although the rate of unintended pregnancies (per 1000 women of childbearing age) is higher in  developing countries , [ 205 ] [ 208 ] [ 209 ]  the percentage of pregnancies that are unintended is actually higher in  developed countries , since a lower proportion of women in developed countries are intending to conceive at any given time. [ 205 ]   Research indicates that unmet need for modern contraception is the cause of 84% of unintended pregnancies in developing countries. [ 210 ]   In the United States, which has a higher unintended pregnancy rate than many other developed nations, [ 211 ]  one important reason that women cite for nonuse of contraceptives is concerns about the side effects of existing products. [ 212 ]   Taken together, these statistics suggests that the current suite of contraceptives is insufficient to meet the fertility planning needs of people across the world, and therefore the introduction of new male contraceptives is likely to decrease the stubbornly high global rates of unintended pregnancy. [ 25 ]


International market research indicates that 49% of men in the United states and 76% of men in Nigeria would try a novel male contraceptive within the first year of its existence. [ 18 ]   Independent modelling predicts that even if real-world usage is only 10% as high as the market research suggests, the introduction of a male contraceptive would avert roughly 200,000 unintended pregnancies per year in the USA and Nigeria each. [ 25 ]


Fathers with unintended births report lower proportions of happiness than in fathers with intentional births [ 213 ]  and unintended fatherhood for men in their early 30's is associated with a significant increase in depressive symptoms. [ 214 ]   In addition, men in insecure financial situations are more likely to report a recent unintended pregnancy, [ 207 ]  and supporting and raising a child brings significant costs that can exacerbate financial insecurity. [ 215 ] [ 216 ]   More broadly, access to effective and reliable contraception would advance men's ability to "maintain personal bodily autonomy, have children, not have children, and parent the children we have in safe and sustainable communities" in accordance with the principles of  Reproductive Justice . [ 217 ]


Family planning has been found to be associated with overall well-being and is one of the most efficient tools for women's empowerment. [ 218 ] [ 219 ] [ 220 ]  Positive outcomes of effective birth control include improvements in women's health, self-agency, education, labor force participation, financial stability, as well as decreases in pregnancy-related deaths, [ 221 ] [ 222 ] [ 223 ]  and these positive social and health impacts may be further realized by the addition of novel male and unisex methods. [ 25 ] [ 18 ]  New male contraceptive options would not come at the expense of women’s reproductive autonomy, since women would still be able to take advantage of all of the contraceptive methods available to them, choose to have both partners use their own contraceptive methods at the same time, or rely solely on their male partners’ form of contraception.


Interventions encouraging male engagement in couples' reproductive health and decisionmaking have shown positive outcomes related to promoting more equitable gender norms in the context of family planning, [ 224 ]  and increased joint decision making in couples. It is reasonable to assume from these data that increasing male involvement as contraceptive users will further improve gender equity. [ 225 ]


While this article has used the term "male" contraception for clarity, these contraceptives are most accurately described as "sperm-targeting" contraceptives, since they would work effectively in any body that produces sperm, regardless of that person's gender identity or external genitalia. [ 17 ]   Importantly, contraceptives that block functions of mature sperm could be delivered in a  unisex  manner, incapacitating sperm before ejaculation in sperm-producing people, or after sperm arrives in the body of egg-producing people. [ 16 ] [ 17 ]


Transgender ,  nonbinary , and  intersex  people are underserved by current contraceptive options.  For example, many trans men can become pregnant (both intentionally and unintentionally), [ 226 ]  but may prefer not to use  estrogen - or  progestin -containing hormonal birth control (both because of the social classification of these hormones as "female sex hormones" and because of a fear they will interfere with  masculinizing hormone therapy , although the American College of Obstetricians and Gynecologists states that these hormonal contraceptives have little effect on masculinization.) [ 227 ] [ 228 ] [ 229 ]  Trans women who have not had  gender-affirming genital surgery  may have similar unmet contraceptive needs as those of  cisgender  men, since gender-affirming hormonal therapy is not effective contraception. [ 229 ]   Nonbinary and intersex people may be less likely to use current methods of birth control, since they are popularly categorized by the labels "male" and "female", which may not match an individual's gender identity or may invoke feelings of  gender dysphoria . [ 228 ]   This dynamic may contribute to the higher rates of unintended pregnancies seen in the  LGBTQ+  community as compared to  heterosexual  peers, [ 230 ] [ 231 ] [ 232 ]  which could in theory be ameliorated by the introduction of  unisex  contraceptives.