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Home , Paradidymis, Testicular pain, Testicular torsion

Original article

Etiology of 2019: Classification into ten logical subgroups Etiología del dolor testicular 2019: Clasificación en diez subgrupos lógicos Juan Fernando Uribe-Arcila,1 Andrés Delgado-Montoya,1* Federico Gaviria-Gil.1

Abstract

Background: Testicular pain encompasses a vast medical diagnostic field, with numerous organ and system convergence. Acute testicular pain is a medical emergency that requires accurate evaluation and immediate resolution, whe- reas chronic testicular pain is enigmatic and requires sound knowledge of the mechanisms of testicular pain and the . Objective: To review the causes of testicular pain and propose a new etiologic classification consisting of 10 subgroups. Methods: A bibliographic search was carried out utilizing Google and the Na- tional Library of Medicine’s PubMed databases to identify original articles and review articles (hard copy or electronic) published on testicular pain, up to March 2020. The search included: MeSH terms: testicular disease (classifica- tion, complications, etiology, trauma, microbiology, pathology, pathophysiolo- gy, secondary, surgery, treatment) and ; Non-MeSH terms: acute and chronic orchialgia, scrotalgia, orchidynia, groin pain, epididymalgia, testalgia, chronic testicular pain, chronic scrotal pain syndrome, testicular pain syndro- me, epididymal pain syndrome, and post-vasectomy pain syndrome. The initial search produced 625 articles, of which 143 were included in the present review. Keywords: Results: To better understand testicular pain etiology, 100 possible diagnoses Pain, Acute pain, were divided into ten subgroups: infectious, neoplastic, traumatic, torsional, vascular, immunologic, neurologic, pharmacologic, obstructive, and miscella- Chronic pain, Visceral neous causes. Likewise, treatment can be divided into two main groups, ac- pain, Scrotal pain, cording to therapeutic options: pharmacologic and non-pharmacologic, with Testicular pain, the latter subdivided into: noninvasive and the increasingly performed invasive Orchialgia (surgical) alternatives. Conclusions: Testicular pain should be understood as a complex pain syndrome of enigmatic origin. Treatment success depends on the correct identification, Correspondence: from hundreds of possibilities, of the cause of pain. Logical grouping of those possibilities could aid in making the accurate etiologic identification. *Andrés Delgado-Mon-

toya. Calle 78b #NO. Citación: Uribe-Arcila J. F., Delgado-Montoya A., Gaviria-Gil F. Etiology of testicular pain 69 - 240, Medellín, 2019: Classification into ten logical subgroups. Rev Mex Urol. 2020;80(4):pp 1-19 Antioquia, Colombia. Email: 1 Hospital Pablo Tobón Uribe, Medellín, Antioquia, Colombia. delgadoandresjkl@ Recepción: July 4, 2019 gmail.com Aceptación: July 26, 2020

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Etiología del dolor testicular 2019: Clasificación en diez subgrupos lógicos..Uribe-Arcila J. F., et al.

Resumen

Introducción: El dolor testicular es un vasto campo de diagnóstico mé- dico, donde convergen múltiples órganos y sistemas. El dolor testicular agudo es una emergencia médica que necesita una evaluación adecuada y una resolución inmediata; pero cuando aparece como un problema crónico, se convierte en un enigma que requiere un buen conocimiento de los mecanismos del dolor testicular y el diagnóstico diferencial. Objetivo: Revisar la etiología del dolor testicular y proponer una nueva clasificación en diez subgrupos etiológicos. Método: Se realizó una búsqueda bibliográfica en Google y las bases de datos National Library of Medicine’s PubMed para identificar artículos originales y de revisión, publicados o publicados electrónicamente, so- bre el dolor testicular, hasta marzo de 2020. Los términos de la búsque- da incluyeron: Términos MESH: Enfermedad testicular (Classificacion, complicationes, etiologia, trauma, microbiologia, patologia, fisiopatolo- gia, secondaria, cirugía, tratamiento) y vasectomia. Términos No MESH: orquialgia aguda y crónica, escrotalgia, orquidinia, inguinalgia, epididi- malgia, testalgia, dolor testicular crónico, síndrome de dolor escrotal crónico, síndrome de dolor testicular, síndrome de dolor epididimario y síndrome de dolor post vasectomía. La búsqueda inicial produjo 625 artículos y 145 se incluyeron en la presente revisión. Resultados: De 100 diagnósticos posibles, para comprender mejor la etiología del dolor testicular, se pueden subdividir en diez subgrupos: infecciosos, neoplásicos, traumáticos, torsionales, vasculares, inmuno- lógicos, neurológicos, farmacológicos, post obstrucción y causas diver- sas. Asimismo, el tratamiento se puede dividir en dos grupos mayores según las opciones terapéuticas: tratamiento farmacológico y no far- macológico, este último con una subdivisión: opciones no invasivas e Palabras clave: invasivas (quirúrgicas) que se están expandiendo. Dolor, Dolor agudo, Conclusiones: El dolor testicular debe entenderse como un síndrome Dolor crónico, Dolor doloroso complejo con un origen enigmático. El éxito del tratamiento visceral, Dolor depende de la correcta identificación de la fuente del dolor; con un cen- escrotal, Dolor tenar de causas posibles, el uso de una agrupación lógica podría facilitar testicular, Orquialgia esta identificación.

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Introduction the genesis of . In 1776, John Hun- ter, an English surgeon, first reported a case Testicular pain is a constant reason for of , and 137 years later, Louis consultation. All medical professionals must Ombrédanne, one of the founders of pediatric be fully equipped with a powerful diagnostic surgery, described testicular appendage torsion vision that requires an open mind and healthy in 1913. In 1922, Colt considered testicular tor- skepticism, to prevent falling into the common sion a surgical emergency.(4–6) limitations of clinical judgment. Lack of awa- reness of the differential diagnosis can lead to errors and confusion with other diseases that Neuroanatomy of the Scrotal Contents share similar symptoms but have different causes and pathophysiology. Therefore, the Sensory innervation of the testis and epidid- present review aims to provide an updated ymis is conducted by autonomic and sensory inventory of the different and ever-changing fibers that travel through the . diagnostic and therapeutic options.(1–3) The somatic fibers of the and the parietal and visceral layers of the travel via the genital branches of the History of Testicular Pain genitofemoral nerve (originating in L1-L2) and ilioinguinal nerve, arising from the first lumbar Testicular pain has been a human concern spinal nerve (L1). Testicular nociceptive fibers throughout history. In ancient Greek mytholo- travel via the sympathetic plexus (T10 to T12), gy, the testes were the preferred human body whereas the deferential and epididymal noci- parts utilized by the gods for tormenting men. ceptive fibers travel via the pelvic plexus (T10 Castration was a religious and medical practice to L1) throughout the .(7–9) for more than 3000 years and is recorded in the old testament. Castrated men, called eunuchs, were employed in imperial palaces to guard Classification of Pain (Origin) the royal harem. In the 16th and 17th centu- ries, prepubescent boys were castrated so they The term orchialgia can often cause some level could remain choir singers, known as castrati, of confusion, since it suggests an exclusively retaining their clear, high, childlike voices. testicular origin (orchio-: testis). In fact, the In 1703 Giovanni Batista Morgagni (1682- origin of intrascrotal pain can be perceived in 1771), considered the father of European the inferior part of the abdomen, the internal anatomy, was the first to describe a hydatid of inguinal ring, the , the back, or the upper the testis, while he was the surgical assistant to part of the thighs, and not necessarily in the Antonio Maria Valsalva at the hospital of Santa testicular body, whereas in some extrascrotal Maria della Morte in Bologna, Italy. Hydatid pathologies, the painful sensation is directly means “drop of water” and Morgagni went to in the testis and its vicinity, altering patient his grave convinced that the rupture of those quality of life. Other more descriptive medical structures, which now bear his name, explained terminology has been employed, such as scro-

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talgia, orchidynia, groin pain, epididymalgia, activating a biochemical cascade that inclu- testalgia, testicular angina, chronic testicular des potassium release, sodium channel al- pain (CTP), chronic scrotal pain syndrome teration, and prostaglandin and bradykinin (CSPS), chronic unexplained orchialgia, and synthesis. Activation causes impulses from enigmatic syndrome, but they all appear to be the stimulated terminals to spread across equally incapable of conveying the complexity the dorsal horn of the spinal cord and other of this painful phenomenon. The testes (and adjacent nerve terminals before it achieves breasts and eyes) are the only organs of the supraspinal neuromodulation. Those ter- body that exhibit the three basic types of pain: minals induce the release of prostaglandin somatic, visceral, and neuropathic: E2, bradykinin, cytokines, chemokines, • Somatic: Somatic pain receptors are found and neuromodulators, such as P substan- in the skin, muscles, and joints. They can ces, that cause vasodilatation and neuronal be subdivided into superficial receptors, in , resulting in an increase of histami- which the stimulus affects skin receptors, ne and serotonin concentrations in the ex- and deep receptors, in which the stimulus tracellular fluid, sensitizing all neighboring is received in the muscular planes, connec- nociceptors and causing an erratic dissemi- tive tissue, or bones. nation of painful sensation. Patients often • Visceral: The visceral nociceptors, which experience hyperalgesia (dissociation be- are mainly composed of unmyelinated affe- tween the magnitude of painful sensation rent fibers, are activated by traction, disten- and the painful stimulus), dysesthesia (di- sion, or . Pain is diffuse and dull. It fficulty in locating the area of the pain) and has an independent component that allows allodynia (pain with stimuli that is typi- it to be sent through a cutaneous area that cally not painful). That repeated process shares the same innervation pathway. explains the genesis of chronic testicular • Neuropathic: The original definition of pain. The pain can be exacerbated by cy- neuropathic pain is “that which originates cling, driving, sitting, horseback riding, or in injury or dysfunction of the nervous by wearing clothing.(10–12) system”. Ever since this first definition, it has undergone constant changes because neuropathic pain is not a single disease, but Testicular Pain (Classification) rather a broad spectrum of signs and symp- toms that alter patient well-being. Its defi- a) Acute orchialgia presents with pain that nition was later modified to be closer to the lasts less than seven days. However, it very pain characteristics previously described. frequently constitutes a urologic emer- The International Association for the Study gency, requiring immediate evaluation of Pain currently defines it as: “pain caused and treatment, hence acute is an by a lesion or disease of the somatosensory appropriate designation. is nervous system.” considered a temporal exception, since, by In that type of pain, the afferent periphe- definition, it is considered an acute diagno- ral nerve fibers respond to the stimulus by sis, with a less-than-six-week progression.

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From the seventh day (acute pain) to the articles on testicular pain, up to March 2020. sixth month (chronic pain), some condi- The search terms included: MeSH terms: tes- tions may be considered subacute and may ticular disease (classification, complications, arise from any of the causes reviewed he- etiology, trauma, microbiology, pathology, rein.(13) pathophysiology, secondary, surgery, and the- b) Chronic orchialgia is constant or intermit- rapy) and vasectomy; Non-MeSH terms: acute tent testicular pain that lasts more than six and chronic orchialgia, scrotalgia, orchidynia, months. All causes of acute pain are poten- groin pain, epididymalgia, testalgia, chronic tial causes of chronic pain, when patients testicular pain (CTP), chronic scrotal pain do not receive adequate diagnoses and syndrome (CSPS), testicular pain syndrome, treatment.(14) epididymal pain syndrome, and post-vasec- The European Association of Urology tomy pain syndrome. The reference list of the (EAU) differentiates four separate syndromes articles retrieved, as well as relevant reviews in its guidelines on chronic pelvic pain:(15) and cases report, were also evaluated. The • Scrotal pain syndrome is the experience initial search produced 615 articles, and after of persistent or recurrent episodic scrotal applying additional filters, 143 studies were pain that is associated with urinary tract or included in the present review. symptoms. There is no epididymo- or other obvious patho- logy. Causes of Testicular Pain • Testicular pain syndrome is the experience of persistent or recurrent episodic pain lo- For better understanding, we recommend divi- cated in the testis upon examination that is ding the causes of acute and chronic testicular associated with urinary tract or sexual dys- pain into ten subgroups, according to the etio- function symptoms. logy of the pain: • Epididymal pain syndrome is the experien- ce of persistent or recurrent episodic pain Subgroup 1: Infectious causes (acute and located in the upon examina- chronic). tion that is associated with urinary tract or Subgroup 2: Tumoral causes (acute and sexual dysfunction symptoms. chronic). • Post-vasectomy pain syndrome is a scrotal Subgroup 3: Traumatic and postoperative pain syndrome that follows vasectomy. causes (acute and chronic). Subgroup 4: Torsional causes (acute and chronic). Evidence Acquisition Subgroup 5: Vascular causes (acute and chronic). A literature search was conducted using Goo- Subgroup 6: Immunologic causes (acute gle and the National Library of Medicine’s and chronic). PubMed databases to identify published hard Subgroup 7: Neurologic causes (acute and copy or electronic original articles and review chronic).

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Subgroup 8: Pharmacologic causes (acute coccidioidomycosis, and echinococcosis), testi- and chronic). cular leprosy (pain appeared in 68% of patients Subgroup 9: Obstructive causes (acute and and testicular compromise was more frequent chronic). in the lepromatous variety (62%) than in the Subgroup 10: Miscellaneous causes (acute dimorphic variety (30%), testicular paludism and chronic). (falciparum), genital tuberculous with suppu- rative changes and fistulas in the scrotal skin, schistosomiasis or filarial orchitis (produced Subgroup 1: Infectious causes by Loa-loa microfilaria, and is usually unilate- ral),(18) granulomatous orchitis, and syphilitic Throughout history, differentiating a surgical orchitis (T. pallidum). emergency, such as torsion, from a medical A testicular abscess is a of emergency, such as epididymitis, has been bacterial epididymo-orchitis in adults, or an important. In 1934, at the St. Albans Naval undiagnosed torsion, trauma, or systemic in- Hospital in New York, Donald Prehn made an fection, such as scarlet , influenza, and interesting observation: testicular pain in sai- typhoid fever, in children. Fournier’s , lors caused by gonococcus was alleviated by or spontaneous gangrene, is a necrotizing infec- elevating the affected , but testicular tion with direct involvement of or secondary pain due to torsion worsened with elevation, extension to the scrotum. It is a relatively pain- ergo, the origin of the classic Prehn sign.(16) less condition because the fasciitis destroys the Epididymitis and epididymo-orchitis are the nerve terminals of the skin. Testicular malako- most frequent causes of acute pain in all ages, plakia is seen in advanced-age patients. It is cha- except for prepubescent boys, in whom there racterized by a painful increase in testicular size are fewer incidences of acute epididymitis. and is diagnosed solely through biopsy, through Infectious etiologies are mostly bacterial, which the Michaelis-Gutmann bodies can be viral, mycobacterial, fungal, or sterile inflam- seen. Chronic /chronic pelvic pain mation of the epididymis that only appears in syndrome (CP/CPPS) is a common disorder in children. In children, the most frequent cause which the two main clinical features are pelvic of orchitis, with severe testicular pain but no pain and lower urinary tract symptoms. Finally, epididymitis, is infection due to the mumps chronic testicular pain may be a component of virus, also called infectia urliana. The clinical urologic chronic pelvic pain syndrome (UC- significance of acute seen in that PPS), previously considered NIH Category 3 scenario can be important, given that it can prostatitis or CPPS, which correctly implies that cause an authentic compartment syndrome of the symptoms are neither due to an infectious the testicular pulp, with a subsequent high risk etiology or an abnormality of the gland. of testicular atrophy. Persistence of infectious There is growing evidence to support several agents or certain types of microbes can cause non-urologic causes, such as myofascial trigger chronic infections. Such infectious agents points, with well recognized referred pain pa- include brucellar epididymo-orchitis,(17) deep tterns (often including the scrotum or testes) mycosis (e.g., actinomycosis, histoplasmosis, and functional somatic syndromes. Functional

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somatic syndromes encompass an enigmatic organ contusions to testicular rupture (a force constellation of pain syndromes that are asso- of 50 kg is required to tear or break the tunica ciated with testicular pain, penile pain, painful albuginea). Traumatic epididymitis is a cause of ejaculation, and reduced sexual function.(19–21) pain, but there are other injuries that aggrava- te pain, such as hematoceles or intratesticular hematomas, tears of the albuginea, laceration Subgroup 2: Tumoral causes of testis, or fractures. Self- orchitis, a less serious condition, may be suspected in Tumor-derived testicular pain is rarely acute. patients that manipulate their own scrotum There is an old medical aphorism that says, to achieve a sensation of pleasure or among “when there is a major injury after a minor patients that compulsively perform self-exa- trauma, a tumor must be ruled out”. During the minations, looking for cancer. Acute, subacute, examination, painful, enlarged testes can be or chronic testicular pain can be triggered after confused with an epididymo-orchitis or testi- any surgery on the genital area or the scrotum, cular torsion. Aside from the classic seminoma- such as herniorrhaphy, varicocelectomy (in- tous and non-seminomatous germ cell tumors, jury or entrapment of nerve branches, passive other diseases less commonly involving neo- congestion of the epididymis and/or testis by plasms of the testis must be considered, such as the sudden diminution of the venous return), lymphomas or leukemia, which may encapsula- spermatocelectomy, orchidopexy (complete or te the cord or . That situation occurs partial), needle biopsy of the testis, or semen more frequently in children or young adults. aspiration for procedures, laparosco- Chronic orchialgia, in the context of a testicular pic donor nephrectomy (can produce ipsilateral tumor, is not rare in underdeveloped countries, orchialgia in 9.6% of men) through various me- where healthcare systems do not routinely chanisms, including the surgical wound, nerve provide screening and its consequently early branch injury, inadequate healing, edema, and diagnosis of in young men. other complications specifically derived from In a culture where preventive healthcare does each of the different procedures. Testicular or not exist, it is not uncommon for men to su- scrotal pain is more often noticed after laparos- ffer from chronic testicular pain caused by the copic repair than after the open delayed diagnosis of testicular tumors. The procedure. Pain following vasectomy has been extramedullary, generally bilateral, testicular reported in 33-56% of patients. The syndrome presentation of multiple myeloma is rare, but is generally recognized as post-vasectomy pain possible, and finally, sarcoidosis can infiltrate syndrome (PVPS), but genuine post-vasec- the testis, producing chronic pain.(22,23) tomy pain syndrome (PVPS) is postoperatively diagnosed in 10% of patients and is also known as post-vasectomy orchialgia or late post-vase- Subgroup 3: Traumatic causes ctomy syndrome. There are a number of theo- ries that explain post-vasectomy pain syndro- Trauma must be considered in all ages as the me: Epididymal congestion, painful spermatic cause of acute pain. Severity varies from simple granuloma, nerve entrapment during healing,

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ejaculatory derangement, or post-vasectomy des testicular appendage torsion. It is generally depression (1%). Epididymitis nodosa is a de- unilateral, but cases of synchronous torsion layed complication after a vasectomy, requiring have been described. Presentation is more additional repair after the rupture of ducts due frequent between 7 and 12 years of age. The to increased pressure caused by the surgery. patient with twisted testicular appendages can Finally, the uncommon, but more severe have a previous history of intermittent pain, dislocation of the testis is a result of trauma even for months. During examination, there is and produces damage or avulsion of the often extreme sensitivity in the superior por- surrounding the testis and/or of the guberna- tion of the testis and the clinical manifestation culum testis. Dislocation is severe in an area is complete with the appearance in the scrotum whose radius is the length of the spermatic of the pathognomonic “blue dot sign”. Four in- cord. The following rupture locations have trascrotal appendages can become twisted: the been reported: superficial inguinal (45%), fe- testicular appendage or hydatid of Morgagni is moral (5%), pubic (18%), penile (8%), inguinal a remnant of Mullerian ducts and is responsible channel (8%), inferior abdominal (4%), supe- for 92% of torsions; an appendage of the head rior abdominal (2%), acetabular (4%), perineal of the epididymis or Haller’s organ is a Wol- (4%), and crural (2%).(15,24–30) ffian remnant and contributes to 7% of torsions; Giralde´s organ, also called the paradidymis or innominate body, another Wolffian remnant, Subgroup 4: Torsional causes accounts for 0.7% of cases; and vas aberrans, a mesonephric remnant, located at the junction Testicular torsion presents in two forms: in- of the body and tail of the epididymis, with a travaginal and extravaginal. The intravaginal 0.3% occurrence (Figure 1).(32) abnormality is the less frequent and presents in newborns up to 15 months, with 72% of Figure 1 cases occurring in the womb. The extravaginal abnormality known as “bell clapper deformi- ty” is commonly seen in emergency services. Paradidymis (0,7%) Inadequate attachment of the tunica vaginalis Epididymal Appendix over the spermatic cord allows the testis to turn (7%) freely on its axis. Intermittent testicular torsion (ITT) should also be considered among the tor- sional causes. Patients that had an episode of acute testicular torsion were reported to have had a previous history of intermittent pain that spontaneously resolved. In most cases of ITT, there is an episode of torsion with spontaneous detorsion.(31) Vas aberrans Testicular (0,3%) The differential diagnosis in acute testicu- Appendix (92%) lar pain, with or without inflammation, inclu-

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Subgroup 5: Vascular causes Subgroup 6: Immunologic causes

Aneurisms of the abdominal aorta, iliac ar- Some immune diseases are potential causes of tery, or testicular arteries can initially start as testicular pain. Autoimmune orchitis is charac- a painful problem. Aortic dissection is also an terized by testicular inflammation and the pre- unusual presentation of severe testicular pain. sence of specific antisperm (ASAs). Henoch-Schoenlein purpura (HSP) is systemic Primary autoimmune orchitis is defined by in- acute vasculitis and its nonrenal genitourinary and asymptomatic orchitis, associated presentation can include scrotal pain and swe- with ASA use (100%) and no systemic disease, lling.(33) Testicular vasculitis is part of a syste- whereas secondary autoimmune orchitis is cha- mic condition of an autoimmune disease, such racterized by symptomatic orchitis and/or tes- as polyarteritis nodosa, which compromises the ticular vasculitis associated with a systemic au- medium and small arteries of the testis, or more toimmune disease. Sweet´s syndrome is acute rarely, Goodpasture syndrome.(34) febrile neutrophilic dermatosis, with a history is the cause of acute or chronic testicular pain. of recurrent fever, noncontagious mouth ulcers Painful varicocele varies from the sensation of (aphthae), phlebitis, pneumonitis, arthritis, weight and annoyance to frank orchialgia. and orchitis with chronic pain. Acute idiopa- The mechanisms of pain are venous stasis, thic scrotal edema is a self-limited condition incompetent valves, and the force of gravity that is usually painless. However, sometimes it when a person stands upright, which increa- is very dramatic and confusing due to the ede- ses testicular congestion.(35) Thrombophlebitis ma and must be considered in the differential of the pampiniform plexus, which is usually diagnosis of other pathologies. The process is unilateral, is an acute condition with intense considered idiopathic, but insect bites, allergy, pain that resembles torsion of the testis or the chemical dermatitis, or trauma can be possible testicular appendages.(36) Splenosis is the disse- causes.(38–40) mination of splenic tissue that can reach up to the inguinal region and cause severe testicular pain that is only alleviated by the removal of Subgroup 7: Neurologic causes the ectopic tissue. Testicular hemangioma is an uncommon and benign condition, with an The diseases included in the neurologic sub- intratesticular arteriovenous malformation group cause pain through direct or indirect irri- that can be a source of pain. Finally, testicular tation of the nerves. Cremasteric muscle spas- is usually segmental, and it is secon- ms with synkinesis cause significant pain and dary to other pathologies with inflammation limit physical activity. Lumbar synchondrosis, and pain. Initial onset can be similar to that of or primary cartilaginous transition joints testicular torsion, with a sudden and lacerating between the thoracic and lumbar vertebrae pain, but it is also described in patients with (T12-L1) or the lumbosacral joint (L5-S1), is falciform anemia or septic embolus during bac- a cause of chronic orchialgia. Pudendal channel terial endocarditis.(37) syndrome with pudendal nerve entrapment gives rise to neuropathy with chronic pain in

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the prostate, scrotum, and rectum. It is caused pain and painful retraction during intercourse. by the compression of the nerve in the sublu- Gadopentetate dimeglumine (Gadolinium) is xation of the levator ani muscle. Adductor ten- used as an intravenous radiocontrast agent to donitis, gluteal fibrosis, or psoas muscle spasm enhance images in nuclear magnetic resonance are potential causes of referred naturopathic imaging,(44) and its fast intravenous injection scrotal pain. has been reported to cause testicular pain. Phantom orchialgia is secondary to radi- The withdrawal of imipramine has also been culitis through irritation of the nerve roots reported to cause testicular angina.(44) Vitamin between T10 and L1. A herniated lumbar disk B12 deficiency has recently been accepted as a produces paroxysmal, radicular pain that is cause of chronic orchialgia.(45) usually subacute upon onset and then becomes chronic. Diabetic neuropathy is a frequent cause of chronic testicular pain. Abdominal Subgroup 9: Obstructive causes epilepsy, or cerebral dysrhythmia, causes acute paroxysmal testicular or as the A group of pathologies with symptoms of main manifestation. Finally, koro-like syndro- ureteral obstruction, such as stones, uretero- me is a psychiatric condition that presents with pelvic junction stricture, retrocaval ureter, anxiety and fear of death, along with genital retroperitoneal fibrosis, constipation, and retraction. A variant of that syndrome includes hydronephrosis, produces referred pain to the symptoms of intense episodic scrotal pain, testis when a nerve is being irritated by intima- with panic attacks.(41,42) te contact of the ureter with the genitofemoral nerve at the L4 spinal level.(46) In abdominal tu- mors and cirrhosis, testicular pain can develop Subgroup 8: Pharmacologic causes due to secondary varicocele. The descending colon, distended with fecal material, and the The mechanism of pharmacologic pain is va- nutcracker phenomenon of the left renal vein riable. For example, epididymitis is associated between the superior mesenteric artery and with visceral pain, but it can also be neuropa- the aorta can produce transitory obstructions thic or chemical. Mazindol is a sympathomime- of the left testicular vein with episodes of pain. tic amine that stimulates the central nervous The nutcracker phenomenon can also lead system and is used as an anorectic.(43) Amioda- to hematuria. rone is a class III antiarrhythmic that blocks the Another group of pathologies produces sodium channels (with a high affinity for open pain due to testicular congestion. In simple hy- and inactivated sodium channels) and potas- drocele, spermatic cord orchialgia is reported sium channels, causing chemical epididymitis when there is underlying inflammation of the and testicular pain. That condition has been testis or epididymis, tension , or when described in up to 11% of adult patients. Desi- hydrocele is secondary to complicated condi- pramine is a tricyclic antidepressant (TCA) tions such as trauma, bleeding, or infection. that inhibits the reuptake of norepinephrine. An epididymal cyst () contains It particularly produces postcoital testicular nonviable semen and is a cause of chronic pain,

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as a result of inflammatory cytokines. Cystic that of acute scrotum, whose symptoms vary degeneration, or testicular microlithiasis, can from painless masses to painful swollen mas- cause chronic orchialgia through different ses. Retractile testis produces testicular pain mechanisms. Pelvic congestion in adolescents when patients feel the testis pulled toward the that are not sexually active and have nocturnal scrotum. Finally, idiopathic scrotal fat emissions is commonly known (in Colombia) is another unusual cause of testicular pain. It is as “fiancé colic”. There are variations in which a characterized by necrosis of the intrascrotal fat, combination of factors produces microtraumas adjacent to the perineum and is typically pre- that result in pain that is not resolved through sent in prepubertal boys, but not in adults.(48–50) sexual activity. Macroorchidism is a disorder in which testicular volume increases to more than 25 cc, as occurs in fragile X syndrome and Treatments Atkin-Flaitz syndrome. Patients usually have mental retardation and a marfanoid phenotype. “While chronic orchialgia may appear to be an Other pathology groups present with insoluble puzzle, the condition can be managed intratesticular obstruction and/or deposit of in an algorithmic fashion”. The objective is to substances and testicular pain. Hyperuricemia quickly define whether treatment should be is a deposit of uric acid crystals in the tubules carried out by the urologist or by a pain mana- of the epididymis that cause pain. Tubular ec- gement specialist. In addition, treatment must tasia of the (TERT) is a benign cystic be gradual (e.g., blockade of the spermatic cord condition of the testis that is mostly seen in before surgery) and the specific causes correc- men over 55 years of age.(47) Ultrasound ima- ted (e.g., varicocele or hernia). ging reveals an intratesticular area containing an abundance of tight and anechoic (cystic) lesions. Constrictive albuginitis causes chronic Pharmacologic treatment options: pain due to fibrosis of the peritubular tissues with a heavy, yellowish, and rigid testicular – Common nonopioid (paraceta- albuginea that shows an excess of hyalinosis mol or acetaminophen) are the first step of and fibrosis. therapeutic management. – Nonsteroidal anti-inflammatory drugs are the second step. Subgroup 10. Miscellaneous causes – analgesics have been considered more useful for inflammatory problems In , the initial manifestation can than for neuropathic pain. appear as acute testicular pain on the right side. – Antimicrobials, according to the site of in- In hemodialysis, an unusual manifestation of fection and the isolated germ. painful testicular ischemia was reported. Testi- – Anticonvulsants or neuroleptics, such as cular pain can also result from indirect inguinal gabapentin, pregabalin, and carbamazepi- and femoral hernias with intra-abdominal con- ne, have been useful in alleviating hyperal- tent. Its clinical manifestation can be similar to gesia and allodynia, which are classic cha-

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racteristics of neuropathic pain. – Psychotherapy or cognitive behavioral the- – α-adrenergic antagonists: alfuzosin, terazo- rapies can attenuate or improve cases of pa- sin, doxazosin, silodosin, or tamsulosin.(51) tients with chronic testicular pain. – Tricyclic antidepressants: several reports – Perineal or pelvic floor massage and the with amitriptyline have indicated symptom release of myofascial trigger points in the improvement.(15) perineum or . – Other antidepressants, such as duloxetine, – Transcutaneous electrical nerve stimula- selective serotonin, and norepinephrine tion (TENS) stimulates certain nerve fibers reuptake inhibitors.(52) to block pain transmission at the central – Allopurinol in hyperuricemia associated level.(56) with testicular pain. – Pulsed radiofrequency. – Vitamin B 12 in cases of deficiency. – Biofeedback therapy.(57) – Analgesia through CB1 cannabinoid recep- tors, located in the area of the spinal cord associated with nociception and calcium Minimally invasive options flow regulation.(53) Although it has not been used in testicular pain, its mechanism – Local anesthetic infiltration of the sperma- appears promising.(54) tic cord, with or without steroids. – Botulinum toxin A in the bilateral cremas- – Local anesthetic infiltration of the pelvic teric muscles in patients with intractable plexus, under TRUS guidance. A mixture of spasm has also been used with hopeful re- lidocaine and steroids can alleviate testicu- sults.(55) lar pain. – Drugs delivered by nanotechnology: the fu- – Needle aspiration of epididymal cyst. ture of testicular therapy. – Direct intraprostatic injection of an anti- biotic, anesthetic, or steroid is a therapeu- tic option to direct pelvic plexus injection. Non-pharmacologic treatment options – Injectable dehydrated amniotic/chorionic membrane allograft (AmnioFix®), a subs- Noninvasive alternatives tance derived from human amniotic mem- brane, has been shown to reduce scar tissue – Pain education: It is always valuable to in- formation.(58) clude education about the causes of pain, – Acupuncture and electroacupuncture have which includes addressing the anxieties been used by practitioners of traditio- that patients with pathology of unknown nal Chinese medicine for more than 2000 etiology have. Information improves treat- years. Their effects may be mediated by ment adherence.(15) neuromodulation to inhibit pain transmis- – Restricted physical activity is a comple- sion, as well as normalize the function of mentary treatment option, especially in ca- various midbrain nuclei.(59) ses of pain that originates in acute inflam- matory scenarios.

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Surgical treatment options – Varicocelectomy, hydrocelectomy, inguinal hernia repair, spermatocelectomy, and or- – Microsurgical spermatic cord denervation chidopexy have been used as treatment for (MSCD) with open, laparoscopic, or ro- patients with the corresponding diagnoses. botic-assisted approaches have been des- – is a “last resort” procedure cribed.(60) for eliminating neuropathic pain, but it also – Pulsed radiofrequency (PRF) denervation has potential risks, including failure to era- of the spermatic cord.(61) dicate the pain.(63) – Ultrasound-guided targeted microcryoa- blation (UTM). Conclusion – Denervation or neurectomy of the ilioin- guinal, iliohypogastric, or genitofemoral Testicular pain is a vast field, in which multiple nerves to improve chronic pain. organs and systems interact. It has numerous – Denervation of the spermatic cord, or cord possible etiologies that include genitourinary stripping, is described in post-vasectomy and non-genitourinary conditions. Clearly, syndrome because exclusive eradication of when there are many diagnostic and therapeu- sympathetic innervations can eliminate the tic options in a clinical situation, only trials sympathetic dystrophy reflex. and training will result in the proper unders- – Spermatic granuloma excision, vasovasos- tanding of chronic pain of the testicle as part tomy or vasoepididymostomy, in post-va- of a complex pain syndrome with an enigmatic sectomy pain syndrome (PVPS). origin, its own biochemical cascades, singular – Decompression for pudendal nerve entrap- pathways, and an unusual variety of signs and ment. symptoms. Given that common analgesics, and – Epididymectomy is a procedure with con- even opiates, fail in the management of testi- tradictory results. It is used in post-vasec- cular pain, the urologist must have a compre- tomy persistent chronic pain, with enlarge- hensive understanding of the patient’s clinical ment of the epididymis.(62) scenario and appropriately select treatment from the wide range of therapeutic options.

Table 1. Testicular pain etiology

ACUTE PAIN CHRONIC PAIN Epididymitis and/or acute orchitis Chronic epididymitis (brucellar, deep mycosis, leprosy, paludism, TBC, syphilis) INFECTIOUS Mumps orchitis Testicular malakoplakia Testicular abscess Chronic prostatitis Fournier’s gangrene

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ACUTE PAIN CHRONIC PAIN Seminoma Seminoma Choriocarcinoma Choriocarcinoma TUMORAL Lymphomas Lymphomas Leukemias Leukemias Acute trauma Post-vasectomy pain syndrome (PVPS) Dislocation of testis Epididymitis nodosa “Self-palpation” orchitis TRAUMATIC AND Post-herniorrhaphy POSTOPERATIVE Post-varicocelectomy Post-spermatocelectomy Post-laparoscopic donor nephrectomy Post-needle biopsy of testis or semen aspiration procedures Torsion of the testis (extravaginal Intermittent testicular torsion and intravaginal) TORSIONAL Perinatal torsion of the spermatic cord Torsion of appendix Aneurysms Varicocele Henoch-Schonlein purpura Sweet´s syndrome Testicular vasculitis Intratesticular arteriovenous malformation VASCULAR AND Acute idiopathic scrotal edema Splenosis INMUNOLOGIC Autoimmune orchitis Thrombophlebitis of the pampiniform plexus Testicular infarction Tendonitis of the inguinal ligament Synchondrosis Adductor tendinitis Pudendal nerve entrapment Psoas spasm Gluteal fibrositis NEUROLOGIC AND Abdominal epilepsy Phantom orchialgia MUSCULOSKELETAL Lumbosacral radiculopathy pain Koro’s syndrome Diabetic neuropathy Pelvic floor tension myalgia

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ACUTE PAIN CHRONIC PAIN Mazindol Mazindol Amiodarone Amiodarone Desipramine Desipramine PHARMACOLOGIC Gadopentetate dimeglumine Gadopentetate dimeglumine (Gadolinium) (Gadolinium) Imipramine withdrawal Imipramine withdrawal Vitamin B12 deficiency Pelvic congestion Inguinal and femoral hernias Appendicitis Retractile testis Meconium periorchitis or Simple or communicating hydrocele vaginalitis Ureteral stones Epididymal cyst (spermatoceles) Ureteropelvic obstruction Hyperuricemia MISCELLANEOUS Retrocaval ureter Macroorchidism Retroperitoneal fibrosis Testicular microlithiasis Hydronephrosis Constrictive albuginitis Hemodialysis Multiple myeloma Constipation Sarcoidosis Idiopathic scrotal fat necrosis Cirrhosis

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