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Varicoceles: prevalence and pathogenesis in adult men

2017; Elsevier BV; Volume: 108; Issue: 3 Linguagem: Inglês

10.1016/j.fertnstert.2017.06.036

1556-5653

Raul I. Clavijo, Robert Carrasquillo, Ranjith Ramasamy,

Sexual Differentiation and Disorders

Varicocele, or dilation of the pampiniform venous plexus, affects up to 15% of men. However, few of these men encounter problems with fertility. This discrepancy between men with varicocele and the number of adversely affected men has led to abundant research to identify the mechanisms for formation of varicocele as well as the pathologic mechanisms by which varicoceles affect fertility potential. In this review, we discuss the prevalence of varicocele in adults, the anatomic features of varicocele, the leading theories as to how varicocele can negatively affect fertility potential, and finally, the current literature on the impact of varicocele on testosterone production. Varicocele, or dilation of the pampiniform venous plexus, affects up to 15% of men. However, few of these men encounter problems with fertility. This discrepancy between men with varicocele and the number of adversely affected men has led to abundant research to identify the mechanisms for formation of varicocele as well as the pathologic mechanisms by which varicoceles affect fertility potential. In this review, we discuss the prevalence of varicocele in adults, the anatomic features of varicocele, the leading theories as to how varicocele can negatively affect fertility potential, and finally, the current literature on the impact of varicocele on testosterone production. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/18168-24269 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/18168-24269 Varicocele is defined as dilation of the pampiniform venous plexus draining the testicle. It is typically diagnosed during a physical exam of the scrotum and graded according to the following scale: grade I varicocele (palpable only during Valsalva maneuver), grade II (palpable in the standing position), and grade III (visible without palpation) (1Dubin L. Amelar R.D. Varicocele size and results of varicocelectomy in selected subfertile men with varicocele.Fertil Steril. 1970; 21: 606-609Abstract Full Text PDF PubMed Scopus (525) Google Scholar). In one of the earliest reviews on varicoceles, written more than 30 years ago, the incidence of varicoceles in healthy men ranged from 4.4% to 22.6%, with an average of 15% (2Saypol D.C. Varicocele.J Androl. 1981; 2: 61-71Crossref Scopus (168) Google Scholar). Interestingly, the prevalence is similar (15.7%) in a contemporary study of 7,035 military recruits (all over 18 years of age) from six European countries. Among men with varicocele, only 1.1% had bilateral disease and 0.2% had isolated right-sided varicocele on physical exam (3Damsgaard J. Joensen U.N. Carlsen E. Erenpreiss J. Blomberg Jensen M. Matulevicius V. et al.Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six European countries.Eur Urol. 2016; 70: 1019-1029Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). On the other hand, the prevalence of varicocele can be as high as 45% among men seeking care for primary infertility and 80% among men seeking care for secondary infertility (4Jarow J.P. Coburn M. Sigman M. Incidence of varicoceles in men with primary and secondary infertility.Urology. 1996; 47: 73-76Abstract Full Text PDF PubMed Scopus (116) Google Scholar, 5Gorelick J.I. Goldstein M. Loss of fertility in men with varicocele.Fertil Steril. 1993; 59: 613-616Abstract Full Text PDF PubMed Google Scholar). Blood from the testicle drains into a network of veins referred to as the pampiniform plexus. With the use of cast preparations, light-microscopic examination, and computer-aided three-dimensional reconstruction, Ergun et al. demonstrated that the veins directly draining the testicle can be separated into two bundles, one of which is a collection of veins tightly wrapped around the testicular artery, and the other in the adjacent fatty tissue (Fig. 1) (6Ergün S. Bruns T. Soyka A. Tauber R. Angioarchitecture of the human spermatic cord.Cell Tissue Res. 1997; 288: 391-398Crossref PubMed Scopus (30) Google Scholar). These two bundles of veins eventually coalesce into the internal spermatic vein at the level of the internal inguinal ring. Dilation of the internal spermatic vein with reflux of blood down into the pampiniform plexus, is thought to be the primary pathologic process for varicocele formation. Rarely, varicoceles can be a result of external compression of the ipsilateral renal vein, or the spermatic vein itself, impeding testicular venous drainage. The dilation and reflux in primary varicocele is thought to occur because of several reasons. First, several venography and cadaver studies confirm that the left, and sometimes right, internal spermatic vein drain into the renal vein, or a suprarenal vein, in a perpendicular fashion (7Asala S. Chaudhary S.C. Masumbuko-Kahamba N. Bidmos M. Anatomical variations in the human testicular blood vessels.Ann Anat. 2001; 183: 545-549Crossref PubMed Scopus (75) Google Scholar). This drainage pattern, along with observations that the left spermatic vein has a longer overall drainage tract and experiences greater venous differences in pressure, may explain the preponderance of left-sided varicoceles and relative scarcity of clinically palpable bilateral and isolated right-sided varicoceles (3Damsgaard J. Joensen U.N. Carlsen E. Erenpreiss J. Blomberg Jensen M. Matulevicius V. et al.Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six European countries.Eur Urol. 2016; 70: 1019-1029Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 8Shafik A. Bedeir G.A. Venous tension patterns in cord veins. I. In normal and varicocele individuals.J Urol. 1980; 123: 383-385Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 9Coolsaet B.L. The varicocele syndrome: venography determining the optimal level for surgical management.J Urol. 1980; 124: 833-839Abstract Full Text PDF PubMed Google Scholar, 10Gat Y. Zukerman Z. Chakraborty J. Gornish M. Varicocele, hypoxia and male infertility. Fluid mechanics analysis of the impaired testicular venous drainage system.Hum Reprod. 2005; 20: 2614-2619Crossref PubMed Scopus (114) Google Scholar). With these anatomic observations it is not surprising that the development of varicoceles has been associated with somatometric parameters that theoretically should alter the length of venous drainage and hydrostatic pressures. In fact, several studies have consistently associated increasing height as a factor associated with the presence of varicoceles, with taller men having a greater prevalence of varicoceles (11Bae K. Shin H.S. Jung H.-J. Kang S.H. Jin B.S. Park J.S. Adolescent varicocele: are somatometric parameters a cause?.Korean J Urol. 2014; 55: 533-535Crossref PubMed Scopus (13) Google Scholar, 12Delaney D.P. Carr M.C. Kolon T.F. Snyder H.M. Zderic S.A. The physical characteristics of young males with varicocele.BJU Int. 2004; 94: 624-626Crossref PubMed Scopus (47) Google Scholar). However, those studies did not define distinct height cutoffs that could predict the presence of varicocele. Second, incompetence of venous valves and variation in internal spermatic vein drainage is postulated as a contributing factor to the development of varicoceles. Early studies in men on postmortem examinations revealed that there was incompetence or absence of internal spermatic vein valves in one-half of the men that were studied (13Ahlberg N.E. Bartley O. Chidekel N. Retrograde contrast filling of the left gonadal vein: a roentgenologic and anatomical study.Acta Radiol Diagn (Stockh). 1965; 3: 385-392Crossref Scopus (55) Google Scholar). More recent studies have shown the complete absence or incompetence of valves in patients with varicoceles (14Dennison A.R. Tibbs D.J. Varicocele and varicose veins compared a basis for logical surgery.Urology. 1986; 28: 211-217Abstract Full Text PDF PubMed Scopus (13) Google Scholar), particularly adolescents (15Vanlangenhove P. Dhondt E. Maele G.V. van Waesberghe S. Delanghe E. Defreyne L. Internal spermatic vein insufficiency in varicoceles: a different entity in adults and adolescents?.Am J Roentgenol. 2015; 205: 667-675Crossref PubMed Scopus (6) Google Scholar). Along these lines, it has been observed that varicoceles may also be caused by the presence of accessory or alternate connections between the internal spermatic vein and systemic venous circulation that lack antirefluxing mechanisms (15Vanlangenhove P. Dhondt E. Maele G.V. van Waesberghe S. Delanghe E. Defreyne L. Internal spermatic vein insufficiency in varicoceles: a different entity in adults and adolescents?.Am J Roentgenol. 2015; 205: 667-675Crossref PubMed Scopus (6) Google Scholar, 16Sze D.Y. Kao J.S. Frisoli J.K. McCallum S.W. Kennedy II, W.A. Razavi M.K. Persistent and recurrent postsurgical varicoceles: venographic anatomy and treatment with N-butyl cyanoacrylate embolization.J Vasc Interv Radiol. 2008; 19: 539-545Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). This anatomic variety must be considered when treating patients at a level far from where testicular veins coalesce (17Nagappan P. Keene D. Ferrara F. Shabani A. Cervellione R.M. Antegrade venography identifies parallel venous duplications in the majority of adolescents with varicocele.J Urol. 2015; 193: 286-290Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar). In fact, this anatomic variety regarding drainage of the internal spermatic vein may be a reason why there is a significantly higher rate of varicocele recurrence after procedures such as laparascopic selective internal spermatic vein ligation and percutaneous venous embolization of the internal spermatic vein (18Halpern J. Mittal S. Pereira K. Bhatia S. Ramasamy R. Percutaneous embolization of varicocele: technique, indications, relative contraindications, and complications.Asian J Androl. 2016; 18: 234-238Crossref PubMed Scopus (40) Google Scholar, 19Al-Kandari A.M. Shabaan H. Ibrahim H.M. Elshebiny Y.H. Shokeir A.A. Comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial.Urology. 2007; 69: 417-420Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Third, a relatively rare mechanism for varicocele formation is compression of the left renal vein or internal spermatic vein (20Lewis D.S. Grimm L.J. Kim C.Y. Left renal vein compression as cause for varicocele: prevalence and associated findings on contrast-enhanced CT.Abdom Imaging. 2015; 40: 3147-3151Crossref PubMed Scopus (8) Google Scholar). Classically, the nutcracker syndrome, where the renal vein is compressed between the aorta and superior mesenteric artery, has been postulated as a possible source of internal spermatic vein insufficiency, some studies associating this condition with the development of varicoceles more in adolescents than in adults and those with lower body mass indexes (15Vanlangenhove P. Dhondt E. Maele G.V. van Waesberghe S. Delanghe E. Defreyne L. Internal spermatic vein insufficiency in varicoceles: a different entity in adults and adolescents?.Am J Roentgenol. 2015; 205: 667-675Crossref PubMed Scopus (6) Google Scholar, 21Handel L.N. Shetty R. Sigman M. The relationship between varicoceles and obesity.J Urol. 2006; 176: 2138-2140Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Importantly, given the possibility of a varicocele being caused by external compression from a tumor or anatomical malformation, such as situs inversus, it is advised that isolated right-sided varicoceles, and potentially new left-sided varicoceles in older men, be worked up with the use of abdominal imaging (20Lewis D.S. Grimm L.J. Kim C.Y. Left renal vein compression as cause for varicocele: prevalence and associated findings on contrast-enhanced CT.Abdom Imaging. 2015; 40: 3147-3151Crossref PubMed Scopus (8) Google Scholar, 22Preziosi P. Miano R. Bitelli M. Ciolfi M.G. Micali S. Micali F. Right varicocele associated with inferior vena cava malformation in situs inversus: percutaneous treatment with retrograde sclerotherapy.J Endourol. 2001; 15: 1001-1003Crossref PubMed Scopus (9) Google Scholar). Anatomically distinct from testicular veins, extrafunicular veins are made up of the cremasteric, external pudendal, gubernacular, and deferential veins, all of which drain into the iliac vein. Although it is advocated that one spare the deferential veins during varicocelectomy (23Goldstein M. Gilbert B.R. Dicker A.P. Dwosh J. Gnecco C. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique.J Urol. 1992; 148: 1808-1811Abstract Full Text PDF PubMed Scopus (377) Google Scholar), ligation of the remaining extrafunicular veins is controversial. Venography provides evidence that makes it unlikely that the extrafunicular veins contribute to pathologic (refluxing) primary or recurrent varicoceles (24Franco G. Iori F. de Dominicis C. dal Forno S. Mander A. Laurenti C. Challenging the role of cremasteric reflux in the pathogenesis of varicocele using a new venographic approach.J Urol. 1999; 161: 117-121Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). However, based on the theory that varicoceles represent an example of a venous retrograde circuit where venous blood flow starts at the incompetent internal spermatic vein and then travels through the pampiniform plexus and out to the pelvic veins, ligation of some these extrafunicular (eg cremasteric) veins may aid in closing this pathologic venous circuit (25Ramasamy R. Schlegel P.N. Microsurgical inguinal varicocelectomy with and without testicular delivery.Urology. 2006; 68: 1323-1326Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Clinically, it seems that attempting to ligate all extrafunicular veins except for the deferential vein by delivering the testicle provides no benefit in terms of improvement of hormonal and semen parameters (25Ramasamy R. Schlegel P.N. Microsurgical inguinal varicocelectomy with and without testicular delivery.Urology. 2006; 68: 1323-1326Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Despite the extensive literature on varicoceles, the precise mechanism by which they can potentially affect spermatogenesis remains elusive. It has been well established that varicoceles are associated with impaired semen parameters even in those not seeking care for infertility (3Damsgaard J. Joensen U.N. Carlsen E. Erenpreiss J. Blomberg Jensen M. Matulevicius V. et al.Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six European countries.Eur Urol. 2016; 70: 1019-1029Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). However, no single theory conclusively explains how varicoceles directly affect spermatogenesis, and most plausible mechanisms have been extrapolated from nonhuman models (26Agarwal A. Hamada A. Esteves S.C. Insight into oxidative stress in varicocele-associated male infertility: part 1.Nat Rev Urol. 2012; 9: 678-690Crossref PubMed Scopus (192) Google Scholar). Here we review the data on the pathologic mechanisms that have been evaluated, including oxidative stress, local hormonal imbalances, stasis of blood (toxin accumulation), testicular hypoperfusion, and heat stress (Fig. 2). Reactive oxygen species (ROS) are highly reactive oxygen-containing chemical species that are unavoidable byproducts of metabolic pathways, such as mitochondrial respiration, which have been observed to impair spermatogenesis (27Sharma R.K. Agarwal A. Role of reactive oxygen species in male infertility.Urology. 1996; 48: 835-850Abstract Full Text PDF PubMed Scopus (759) Google Scholar). Mitochondria are thought to be the main source of sperm-produced ROS, particularly in the formation of superoxide in the electron transport chain (28Amaral A. Lourenço B. Marques M. Ramalho-Santos J. Mitochondria functionality and sperm quality.Reproduction. 2013; 146: R163-R174Crossref PubMed Scopus (328) Google Scholar). Excessive ROS production has been associated with reduced sperm motility, abnormal sperm morphology, and decreased sperm adenosine triphosphate (ATP) production (29Gvozdjáková A. Kucharská J. Dubravicky J. Mojto V. Singh R.B. Coenzyme Q10, α-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility.Dis Markers. 2015; 2015: 827941Crossref PubMed Scopus (52) Google Scholar). ROS may also affect less mature spermatogonia by causing damage to DNA and chromatin structure, potentially leading to germ cell apoptosis (30Agarwal A. Mulgund A. Alshahrani S. Assidi M. Abuzenadah A.M. Sharma R. et al.Reactive oxygen species and sperm DNA damage in infertile men presenting with low level leukocytospermia.Reprod Biol Endocrinol. 2014; 12: 126Crossref PubMed Scopus (91) Google Scholar). Varicoceles are associated with the presence of higher oxidative stress in the semen of patients seeking care for infertility (31Agarwal A. Prabakaran S. Allamaneni S.S. Relationship between oxidative stress, varicocele and infertility: a meta-analysis.Reprod Biomed Online. 2006; 12: 630-633Abstract Full Text PDF PubMed Scopus (176) Google Scholar). Abnormally high levels of ROS can increase DNA fragmentation (30Agarwal A. Mulgund A. Alshahrani S. Assidi M. Abuzenadah A.M. Sharma R. et al.Reactive oxygen species and sperm DNA damage in infertile men presenting with low level leukocytospermia.Reprod Biol Endocrinol. 2014; 12: 126Crossref PubMed Scopus (91) Google Scholar, 32Lopes S. Jurisicova A. Sun J.G. Casper R.F. Reactive oxygen species: potential cause for DNA fragmentation in human spermatozoa.Hum Reprod. 1998; 13: 896-900Crossref PubMed Scopus (429) Google Scholar). In turn, compromise in DNA integrity can then lead to decreased fertility potential and may serve as the link between varicoceles and impaired semen quality (32Lopes S. Jurisicova A. Sun J.G. Casper R.F. Reactive oxygen species: potential cause for DNA fragmentation in human spermatozoa.Hum Reprod. 1998; 13: 896-900Crossref PubMed Scopus (429) Google Scholar, 33Erenpreiss J. Hlevicka S. Zalkalns J. Erenpreisa J. Effect of leukocytospermia on sperm DNA integrity: a negative effect in abnormal semen samples.J Androl. 2002; 23: 717-723PubMed Google Scholar), especially given the evidence that varicocelectomy can decrease sperm DNA fragmentation and increase fertility potential (34Esteves S.C. Sánchez-Martín F. Sánchez-Martín P. Schneider D.T. Gosálvez J. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm.Fertil Steril. 2015; 104: 1398-1405Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 35Kirby E.W. Wiener L.E. Rajanahally S. Crowell K. Coward R.M. Undergoing varicocele repair before assisted reproduction improves pregnancy rate and live birth rate in azoospermic and oligospermic men with a varicocele: a systematic review and meta-analysis.Fertil Steril. 2016; 106: 1338-1343Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Unfortunately, the reference ranges for both ROS and DNA fragmentation can vary widely depending on the assay used in the laboratory. Testicular biopsies from men with varicoceles have provided histologic evidence that this condition leads to stagnation of blood in microcirculatory vessels, resulting in ischemic structural changes at the cellular level (10Gat Y. Zukerman Z. Chakraborty J. Gornish M. Varicocele, hypoxia and male infertility. Fluid mechanics analysis of the impaired testicular venous drainage system.Hum Reprod. 2005; 20: 2614-2619Crossref PubMed Scopus (114) Google Scholar, 36Chakraborty J. Hikim A.P.S. Jhunjhunwala J.S. Stagnation of blood in the microcirculatory vessels in the testes of men with varicocele.J Androl. 1985; 6: 117-126Crossref PubMed Scopus (67) Google Scholar). Evidence of hypoxia in men with varicoceles has been investigated at the molecular level as well, with one study noting a higher expression of hypoxia-inducible factor 1α, a key regulator in tissue response to hypoxia, in internal spermatic vein samples (37Lee J.-D. Jeng S.-Y. Lee T.-H. Increased expression of hypoxia-inducible factor-1α in the internal spermatic vein of patients with varicocele.J Urol. 2006; 175: 1045-1048Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Another source of support of the theory that varicoceles decrease local blood flow in the testicle are studies demonstrating improved testicular arterial hemodynamics after varicocelectomy (38Tarhan S. Ucer O. Sahin M.O. Gumus B. Long-term effect of microsurgical inguinal varicocelectomy on testicular blood flow.J Androl. 2011; 32: 33-39Crossref PubMed Scopus (37) Google Scholar, 39Zhang M. Du L. Liu Z. Qi H. Chu Q. The effects of varicocelectomy on testicular arterial blood flow: laparoscopic surgery versus microsurgery.Urol J. 2014; 11: 1900-1906PubMed Google Scholar). There is significant evidence that scrotal hyperthermia leads to impairment of spermatogenesis as evident from the literature evaluating heat stress as contraception as well as the effect of fevers on spermatogenesis (40Jung A. Schuppe H.-C. Influence of genital heat stress on semen quality in humans.Andrologia. 2007; 39: 203-215Crossref PubMed Scopus (188) Google Scholar). Several human and animal studies have measured significantly increased intratesticular and scrotal skin temperature associated with varicoceles (41Goldstein M. Eid J.F. Elevation of intratesticular and scrotal skin surface temperature in men with varicocele.J Urol. 1989; 142: 743-745Abstract Full Text PDF PubMed Scopus (177) Google Scholar, 42Green K.F. Turner T.T. Howards S.S. Varicocele: reversal of the testicular blood flow and temperature effects by varicocele repair.J Urol. 1984; 131: 1208-1211Abstract Full Text PDF PubMed Scopus (68) Google Scholar). Theories as to how varicoceles increase testicular temperature mostly revolve around the model of scrotal countercurrent heat exchange proposed by Dahl et al. where heat is exchanged above the testicle between vessels carrying blood to the testicle and vessels exiting the testicle (43Dahl E.V. Herrick J.F. A vascular mechanism for maintaining testicular temperature by counter-current exchange.Surg Gynecol Obstet. 1959; 108: 697-705PubMed Google Scholar). Molecular mechanisms for how heat stress leads to impairment in spermatogenesis includes decreased production of proteins overall and specifically key enzymes, such as topoisomerase I, DNA polymerase, and heat shock proteins (44Hosseinifar H. Gourabi H. Salekdeh G.H. Alikhani M. Mirshahvaladi S. Sabbaghian M. et al.Study of sperm protein profile in men with and without varicocele using two-dimensional gel electrophoresis.Urology. 2013; 81: 293-300Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 45Fujisawa M. Yoshida S. Kojima K. Kamidono S. Biochemical changes in testicular varicocele.Arch Androl. 1989; 22: 149-159Crossref PubMed Scopus (56) Google Scholar). Given the importance of adequate serum levels of testosterone to spermatogenesis and fertility, it has been hypothesized that varicoceles impair normal Leydig cell function and number, and in turn Sertoli cell function. Repair of varicoceles can restore normal serum androgen levels with reversal of symptomatic hypogonadism and impaired spermatogenesis. The relationship between varicocele repair and serum testosterone was documented as early as the 1970s (46Comhaire F. Vermeulen A. Plasma testosterone in patients with varicocele and sexual inadequacy.J Clin Endocrinol Metab. 1975; 40: 824-829Crossref PubMed Scopus (134) Google Scholar). We now understand testicular function to be temperature dependent, and the aforementioned pathogenic mechanisms of varicoceles, including toxin accumulation, heat stress, and oxidative stress, may directly affect the Leydig cell population of the testis responsible for the normal intratesticular testosterone concentrations needed for spermatogenesis (47Naughton C.K. Nangia A.K. Agarwal A. Varicocele and male infertility: Part II: pathophysiology of varicoceles in male infertility.Hum Reprod Update. 2001; 7: 473-481Crossref PubMed Scopus (311) Google Scholar). Leydig cells are the principal androgen-producing cells in mammals, contributing 95% of total serum testosterone secretion in adult men. Testosterone is the end-product of a five-step enzymatic pathway under direct stimulation of LH produced by the pituitary gland (48Dabaja A. Wosnitzer M. Goldstein M. Varicocele and hypogonadism.Curr Urol Rep. 2013; 14: 309-314Crossref PubMed Scopus (22) Google Scholar). LH stimulates intracellular cyclic AMP–protein kinase A signaling, which promotes trafficking of cholesterol precursor from the cytoplasm to mitochondria by way of steroidogenic acute regulatory protein (StAR) (49Clark B.J. Wells J. King S.R. Stocco D.M. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR).J Biol Chem. 1994; 269: 28314-28322Abstract Full Text PDF PubMed Google Scholar, 50Miller W.L. Auchus R.J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders.Endocr Rev. 2011; 32: 81-151Crossref PubMed Scopus (1369) Google Scholar). Trafficking of cholesterol by StAR is a rate-limiting step in testosterone biosynthesis, and in vitro studies have demonstrated inhibition of StAR protein expression and activity during oxidative stress (51Diemer T. Allen J.A. Hales K.H. Hales D.B. Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis.Endocrinology. 2003; 144: 2882-2891Crossref PubMed Scopus (268) Google Scholar). In vivo studies in mice have demonstrated a significant decrease in serum and intratesticular levels of testosterone when challenged with chronic hypoxia, which is known to cause elaboration of ROS in gonadal tissue (52Barnholt K.E. Hoffman A.R. Rock P.B. Muza S.R. Fulco C.S. Braun B. et al.Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction.Am J Physiol Endocrinol Metab. 2006; 290: E1078-E1088Crossref PubMed Scopus (99) Google Scholar, 53Farias J.G. Bustos-Obregón E. Tapia P.J. Gutierrez E. Zepeda A. Juantok C. et al.Time course of endocrine changes in the hypophysis-gonad axis induced by hypobaric hypoxia in male rats.J Reprod Dev. 2008; 54: 18-21Crossref PubMed Scopus (41) Google Scholar). A similar phenomenon has been described in human patients with obstructive sleep apnea and long-term exposure to high altitude, which are coincident with decreases in serum testosterone and oligozoospermia (54Benso A. Broglio F. Aimaretti G. Lucatello B. Lanfranco F. Ghigo E. et al.Endocrine and metabolic responses to extreme altitude and physical exercise in climbers.Eur J Endocrinol. 2007; 157: 733-740Crossref PubMed Scopus (102) Google Scholar, 55Liu P.Y. Caterson I.D. Grunstein R.R. Handelsman D.J. Androgens, obesity, and sleep-disordered breathing in men.Endocrinol Metab Clin North Am. 2007; 36: 349-363Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Heat stress to the testes as a result of varicocele affects testicular function. Recent nonhuman studies demonstrate a direct toxic effect on the viability of Leydig cells and testosterone production after heat stress. Normal heat stress responses on the cellular level are mediated by the endoplasmic reticulum, an organelle essential to maintaining cellular homeostasis under stress conditions, which activates an intracellular cascade known as the unfolded protein response (56Schröder M. Kaufman R.J. ER stress and the unfolded protein response.Mutat Res. 2005; 569: 29-63Crossref PubMed Scopus (1395) Google Scholar). This stress response allows for detection of heat-induced protein misfolding, and subsequent degradation of these proteins with a halt to protein translation. When this heat stress is chronic in nature, the unfolded protein response cascade has been shown to also activate proapoptotic pathways leading to cell death (57Wang X.Z. Lawson B. Brewer J.W. Zinszner H. Sanjay A. Mi L.J. et al.Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).Mol Cell Biol. 1996; 16: 4273-4280Crossref PubMed Scopus (604) Google Scholar). In 2016, investigators used tissue culture and live mouse models to investigate the effect of heat stress on Leydig cell function and viability (58Kim J.H. Park S.J. Kim T.S. Kim J.M. Lee D.S. Testosterone production by a Leydig tumor cell line is suppressed by hyperthermia-induced endoplasmic reticulum stress in mice.Life Sci. 2016; 146: 184-191Crossref PubMed Scopus (33) Google Scholar). With the use of a tissue culture cell line of mouse Leydig tumor cells responsive to hCG, they demonstrated a clear increase in stress response mediator proteins and a concordant decrease in hCG-induced steroidogenic activity. Levels of hormone product as well as key enzyme levels in the testosterone synthetic pathway were diminished. With the use of a live mouse model, this heat stress–mediated decrease in steroidogenesis was recapitulated. Steroidogenic enzymes, including StAR, and serum levels of testosterone were decreased in mice after several cycles of heat exposure to 42°C for 15 minutes per day. Decreased steroidogenic enzymes and serum testosterone was reversible by the administration of tauroursodeoxycholic acid (TUDCA), a known endoplasmic reticulum stress inhibitor, injected intraperitoneally. At the histologic level, mice undergoing repeated heat stress exhibited Leydig cell death and activation of proapoptotic cellular cascades within Leydig cells, again reversible with administration of the TUDCA stress-inhibiting agent. Multiple nonhuman animal models have been published confirming a direct pathologic consequence of anatomic varicoceles on Leydig cell viability. Luo et al. performed a sham-controlled experiment in rats with surgically induced left-sided varicoceles (59Luo D.Y. Yang G. Liu J.J. Yang Y.R. Dong Q. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells.Asian J Androl. 2011; 13: 287-291Crossref PubMed Scopus (65) Google Scholar). Biochemical studies on these rats at 4 and 8 weeks after induction of varicocele demonstrated apoptosis of Leydig cells and decreased testosterone biosynthesis, with intratesticular levels markedly reduced in the varicocele group versus the sham group at 8 weeks (24.84 vs. 29.41 ng/g; P<.05). Immunohistochemical evaluation in that study showed a statistically significant increase in Leydig cell apoptotic index in the varicocele group compared with sham control at 4 and 8 weeks (P<.01), and StAR mRNA expression levels were significantly decreased in the varicocele group compared with sham control. Very interestingly, a similar decrease in StAR mRNA expression was seen in the right (normal) testis compared with the left (varicocele) testis in the experimental group, suggestive of a systemic consequence to surgically induced varicocele. Other enzymatic dysfunction has been demonstrated in rodent models; experimental varicocele induction in one experiment was shown to inhibit testosterone production by Leydig cells at the 17,20-desmolase step in the biosynthetic pathway (60Rajfer J. Turner T.T. Rivera F. Howards S.S. Sikka S.C. Inhibition of testicular testosterone biosynthesis following experimental varicocele in rats.Biol Reprod. 1987; 36: 933-937Crossref PubMed Scopus (93) Google Scholar). The utility of varicocelectomy also has been demonstrated in nonhuman models. Ozturk et al. (61Ozturk M.I. Koca O. Keles M.O. Haklar G. Baykan O. Ercan F. et al.The impact of unilateral experimental rat varicocele model on testicular histopathology, Leydig cell counts, and intratesticular testosterone levels of both testes.Urol J. 2013; 10: 973-980PubMed Google Scholar) conducted a study involving rats with a surgically induced varicocele without repair, and a surgically induced varicocele with repair at 4 weeks. Intratesticular testosterone levels were assessed at 8 weeks (4 weeks after repair) and there was a statistically significant increase of serum testosterone in the repair group compared with rats that did not have varicocelectomy, indicating that repair allows for reversal of varicocele-related hypogonadism. In the context of adult humans, multiple studies have been published demonstrating a clear effect of varicocele repair on serum testosterone levels, beginning in 1995 with a retrospective study by Su et al. (62Su L.M. Goldstein M. Schlegel P.N. The effect of varicocelectomy on serum testosterone levels in infertile men with varicoceles.J Urol. 1995; 154: 1752-1755Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Those investigators reported an increase in total serum testosterone from 319 ± 12 ng/dL preoperatively to 409 ± 23 ng/dL (P<.0004) after inguinal or subinguinal microsurgical varicocele repair in 33 men presenting with infertility. Since that time, other studies corroborated these findings (25Ramasamy R. Schlegel P.N. Microsurgical inguinal varicocelectomy with and without testicular delivery.Urology. 2006; 68: 1323-1326Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 63Cayan S. Kadioglu A. Orhan I. Kandirali E. Tefekli A. Tellaloglu S. The effect of microsurgical varicocelectomy on serum follicle stimulating hormone, testosterone and free testosterone levels in infertile men with varicocele.BJU Int. 1999; 84: 1046-1049Crossref PubMed Google Scholar, 64Tanrikut C. Goldstein M. Rosoff J.S. Lee R.K. Nelson C.J. Mulhall J.P. Varicocele as a risk factor for androgen deficiency and effect of repair.BJU Int. 2011; 108: 1480-1484Crossref PubMed Scopus (115) Google Scholar, 65Gat Y. Gornish M. Belenky A. Bachar G.N. Elevation of serum testosterone and free testosterone after embolization of the internal spermatic vein for the treatment of varicocele in infertile men.Hum Reprod. 2004; 19: 2303-2306Crossref PubMed Scopus (36) Google Scholar) whereas others failed to demonstrate an increase in serum testosterone after varicocelectomy (66Pasqualotto F.F. Lucon A.M. de Góes P.M. Sobreiro B.P. Hallak J. Pasqualotto E.B. et al.Is it worthwhile to operate on subclinical right varicocele in patients with grade II–III varicocele in the left testicle?.J Assist Reprod Genet. 2005; 22: 227-231Crossref PubMed Scopus (33) Google Scholar, 67Di Bisceglie C. Bertagna A. Baldi M. Lanfranco F. Tagliabue M. Gazzera C. et al.Varicocele sclerotherapy improves serum inhibin B levels and seminal parameters.Int J Androl. 2007; 30: 531-536Crossref PubMed Scopus (30) Google Scholar, 68Ozden C. Ozdal O.L. Bulut S. Guzel O. Koyuncu H.H. Memis A. Effect of varicocelectomy on serum inhibin B levels in infertile patients with varicocele.Scand J Urol Nephrol. 2008; 42: 441-443Crossref PubMed Scopus (27) Google Scholar). It is worthwhile to note, however, that in the studies suggesting no effect of varicocele repair, a majority of patients had normal preoperative serum testosterone levels, and change in serum testosterone was a secondary outcome measure, perhaps undermining the ability of those studies to detect a change owing to insufficient statistical power and variability in measurement of serum testosterone levels. Recent prospective studies appear to confirm a statistically significant increase in serum testosterone after varicocelectomy in hypogonadal men (69Zohdy W. Ghazi S. Arafa M. Impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility.J Sex Med. 2011; 8: 885-893Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 70Sathya Srini V. Belur Veerachari S. Does varicocelectomy improve gonadal function in men with hypogonadism and infertility? Analysis of a prospective study.Int J Endocrinol. 2011; 2011: 916380Crossref PubMed Scopus (48) Google Scholar, 71Abdel-Meguid T.A. Farsi H.M. Al-Sayyad A. Tayib A. Mosli H.A. Halawani A.H. Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: a prospective controlled study.Urology. 2014; 84: 1081-1087Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), and a 2012 meta-analysis of nine studies with a total of 814 men showed a mean increase in serum testosterone of 97.48 ng/dL (95% confidence interval [CI] 43.73–151.22; P=.0004) from preoperative levels (72Li F. Yue H. Yamaguchi K. Okada K. Matsushita K. Ando M. et al.Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis.Int J Urol. 2012; 19: 149-154Crossref PubMed Scopus (65) Google Scholar). Whether this increase in serum testosterone of 100 ng/dL translates into improvement of clinically significant symptoms remains to be seen. In reviewing what is known about varicoceles in adults, it is clear varicoceles are not only prevalent but also pathologic, leading to impairment of semen parameters and testosterone production. It is important to understand the anatomy of varicoceles, particularly the variety of venous drainage paths, because it can determine how effective treatment options are, especially if one chooses embolization or high ligation of the internal spermatic vein. Looking at molecular pathogenic mechanisms as they relate to impairment of semen parameters and testosterone production, it is clear that there are several plausible theories that still remain unproven. Nevertheless, it is important for clinicians to understand the anatomy and mechanism by which varicocele affects testicular function, because it will help with choosing the ideal treatment option and in the discussion of causes of recurrence and complications when counseling patients.