Inheritance of varicoceles

doi:10.1016/j.urology.2004.12.057

Urology

Volume 65, Issue 6, June 2005, Pages 1186-1189

https://doi.org/10.1016/j.urology.2004.12.057 Get rights and content

Abstract

Objectives

To evaluate the inheritance of varicoceles through examination of first-degree relatives of patients with known varicoceles.

Methods

A total of 44 patients with a known varicocele had available first-degree relatives (n = 62) examined for the presence of a varicocele between October 1997 and November 2003. An additional cohort of 263 men presenting for vasectomy reversal without a history of subfertility or varicocele was used as the control group. Varicocele grade and the presence of bilateral varicoceles were examined as predictive factors for inheritance.

Results

Of the 62 first-degree relatives of patients with a known varicocele, 35 (56.5%) had a clinically palpable varicocele on physical examination. This was significantly greater than the 18 (6.8%) of 263 men in the control group (P <0.0001). Of the first-degree relatives, 20 (74%) of 27 brothers, 13 (41%) of 32 fathers, and 2 (67%) of 3 sons had palpable varicoceles. Neither varicocele grade nor bilaterality was predictive of inheritance in these first-degree relatives.

Conclusions

The increase in varicocele prevalence is significant in the first-degree relatives (particularly brothers) of patients with known varicoceles. Given the detrimental effect of varicoceles on spermatogenesis and steroidogenesis, patients should be counseled about this increased risk in male family members.

Section snippets

Patient selection

We retrospectively reviewed the charts of men presenting to a tertiary care university center between October 1997 and November 2003 and identified those patients diagnosed with a palpable varicocele during an evaluation of subfertility. Of the these men, 44 agreed to have their available first-degree relatives contacted for screening of varicoceles. Of the 106 first-degree relatives contacted, 62 (58.5%) elected to participate in this study. All first-degree relatives included in this study

Results

The characteristics of the study participants are presented in Table I.

Comment

Varicoceles have been described in the medical literature since the first century. Most of the studies of varicoceles have focused on its pathophysiology, as well as on the methods and results of repair.11, 12, 13, 14, 15 The heredity of varicoceles and the potential transmission to first-degree relatives has rarely been addressed.

To our knowledge, this study is the largest to date to evaluate the inheritance of varicoceles. We found that more than 50% of first-degree relatives of patients with

Conclusions

On the basis of the known estimates of the incidence of varicoceles in the general population, as well as the comparison with our control group, a significant increase in varicocele prevalence is present in the first-degree relatives (particularly brothers) of men with known varicoceles. Neither varicocele size nor bilaterality appeared to increase the risk of inheritance. Given the detrimental effect of varicoceles on spermatogenesis and steroidogenesis, patients should be counseled about this

Acknowledgment

To Paul Christos, M.S., M.P.H., Department of Biostatistics and Epidemiology, Weill-Cornell University Medical Center, who provided assistance with the statistical analysis for this manuscript.

References (16)

J.I. Gorelick et al.
Loss of fertility in men with a varicocele
Fertil Steril
(1993)
M.A. Witt et al.
Varicocelea progressive or static lesion?
Urology
(1993)
M.M. Wishahi
Detailed anatomy of the internal spermatic vein and the ovarian veinhuman cadaver study and operative spermatic venography—clinical aspects
J Urol
(1991)
C. Beinart et al.
Left renal vein to inferior vena cava pressure relationships in humans
J Urol
(1982)
R.M. Harrison et al.
Pathophysiology of varicocele in nonhuman primateslong-term seminal and testicular changes
Fertil Steril
(1986)
A.W. Zorgniotti et al.
Studies in temperature, human semen quality, and varicocele
Fertil Steril
(1973)
M. Goldstein et al.
Elevation of intratesticular and scrotal skin surface temperature in men with a varicocele
J Urol
(1989)
J. MacLeod
Seminal cytology in the presence of varicocele
Fertil Steril
(1965)

There are more references available in the full text version of this article.

Cited by (49)

Exosomes as Potential Biomarkers for Erectile Dysfunction, Varicocele, and Testicular Injury
2022, Sexual Medicine Reviews
Optimal male reproductive health is dependent upon critical mediators of cell-cell communication: exosomes or extracellular vesicles. These vesicles are nano‐sized particles released into a variety of bodily fluids, such as blood and semen. Exosomes are highly stable and can carry genetic and other molecules, including DNA, RNA, and proteins, which provide information about their origin cells.
To identify exosomes as potential biomarkers or therapeutic mediators in male sexual and reproductive disorders like erectile dysfunction (ED), varicocele, and testicular injury.
A PubMed search was performed to highlight all articles available relating to exosomes and extracellular vesicles in the pathogenesis of different male sexual and reproductive disorders, and their importance in clinical use as both diagnostic markers and potential therapeutic mediators.
Various male reproductive system disorders, such as ED, varicocele, and testicular injury, are linked to increased or decreased levels of exosomes. Exosomes have a higher number of molecules such as DNA, RNA, and proteins, which can give a more precise and comprehensive result when compared to other biomarkers. Exosomes can be considered as plausible diagnostic biomarkers for male sexual and reproductive diseases, with considerable advantages over other diagnostic procedures such as invasive tissue biopsy. Exosomes can carry cargo such certain drugs and therapeutic molecules making them a promising therapeutic approach. Several studies have begun to test treating various male sexual reproductive disorders with exosomes.
Exosomes deliver many components that can regulate gene expression and target signaling pathways. Understanding how extracellular vesicles can be utilized as biomarkers in diagnosing men, particularly those with idiopathic erectile dysfunction, will not only aid in diagnosis but also help with making therapeutic targets.
Khodamoradi K, Golan R, Dullea A, et al. Exosomes as Potential Biomarkers for Erectile Dysfunction, Varicocele, and Testicular Injury. Sex Med Rev 2022;10:311–322.
Characterization of varicocele-induced animal models: Potential role of inflammasome complex in the varicocele pathophysiology
2022, Journal of Reproductive Immunology
Citation Excerpt :
Despite, a study that evaluated first-degree relatives of men with varicocele, found that around 34 % had palpable varicocele, which was approximately 3-fold greater than the control population (Gökçe et al., 2010). As previously reviewed (Alsaikhan et al., 2016), heredity for varicocele has already shown a prevalence of 45 and 56 % (Mokhtari et al., 2008; Raman et al., 2005). Although the study of Gökçe et al. (2010) evaluated a small cohort (100 men with varicocele), multicenter studies with larger cohorts could help to strengthen this finding (Gökçe et al., 2010).
Varicocele mechanisms and its impact in testicular dysfunction has been studied in order to understand the pathophysiology involved in this disease. However, study designs using testicular tissues from varicocele patients are restricted due to ethical limitations. Therefore, the use of animal models, mainly rats, that mimics varicocele and its effects is an option to develop new approaches. The surgical technique, that induces the varicocele in rats, is based on the partial obstruction of the left renal vein, leading to a dilation in the left spermatic vein and consequently to the pampiniform plexus, resulting in varicocele-induced condition. Thus, the study of the cellular and molecular mechanisms involved in varicocele development can be addressed in depth. Besides the animal model goal to uncover the exact varicocele pathophysiology, varicocele induced models are the best options to develop new non-surgical and less invasive therapies. Various animal model studies designed and investigated antioxidant and anti-inflammatory agents to face varicocele conditions. Minding this fact, we tried to discuss a newly uncovered complex in varicocele condition, known as inflammasome complex. Taking into consideration the possible inflammatory state present in varicocele, the inflammasome complex has been proposed to be involved in the pathophysiology of this disease.
Effect of varicoceles on spermatogenesis
2022, Seminars in Cell and Developmental Biology
Citation Excerpt :
There also exists a genetic component to varicocele pathology. It has been reported that those with first-degree relatives have higher rates of varicocele, with one study reporting rates in brothers of men with varicocele at greater than 50% [15,16]. However, no genetic factors have been identified that explain the inheritance of varicocele occurrence or grade [16].
Varicoceles are dilated veins within the spermatic cord and a relatively common occurrence in men. Fortunately, the large majority of men are asymptomatic, however, a proportion of men with varicoceles can suffer from infertility and testosterone deficiency. Sperm and testosterone are produced within the testis, and any alteration to the testicular environment can negatively affect the cells responsible for these processes. The negative impact of varicoceles on testicular function occurs mainly due to increased oxidative stress within the testicular parenchyma which is thought to be caused by scrotal hyperthermia, testicular hypoxia, and blood-testis barrier disruption. Management of varicoceles involves ligation or percutaneous embolization of the dilated veins. Repair of varicoceles can improve semen parameters and fertility, along with serum testosterone concentration. In this review, we discuss the pathophysiology of varicoceles, their impact on testicular function, and management.
Molecular characteristics of varicocele: integration of whole-exome and transcriptome sequencing
2021, Fertility and Sterility
To explore the exome and transcriptome characteristics potentially underlying the pathogenesis of varicocele (VE).
Experimental study and cohort study.
Academic research laboratory and university-affiliated hospital.
Eleven VE patients whose fathers also had VE, plus 151 additional patients and 324 healthy men for variants genotyping; for the rat model, eight Sprague–Dawley male rats.
Partial ligation of renal vein was conducted to establish VE rat models for whole-transcriptome RNA sequencing (RNA-seq).
Genes with differential expression and/or harboring potential pathogenic variants detected via RNA-seq and whole-exome sequencing (WES) then subjected to population-based survey to define candidate genes of VE and analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes to identify VE-involved pathways.
Whole-transcriptome RNA sequencing (RNA-seq) was performed using left spermatic veins of five rat VE models and three controls. We identified 9,688 genes and 18 pathways via RNA-seq, and via WES 160 genes harboring 279 potential deleterious variants and 16 pathways. Nine genes (AAMP, KMT2D, IRS2, SPINT1, IFT122, MKI67, DCHS1, LAMA2, and CBL) had variants in more than one patient who underwent WES, and six of these genes (AAMP, SPINT1, MKI67, IFT122, LAMA2, and DCHS1) showed differential expression. The population-based survey showed that AAMP, SPINT1, and MKI67 were strongly associated with VE risk. Together, two omic 67 data sets revealed four pathways potentially related to VE.
For the first time, we have described the exome and transcriptome characteristics of VE. The bi-omics identified novel candidate genes and pathways involving the occurrence and development of VE.
Caracteres moleculares del varicocele: integración del genoma completo y de la secuenciación del transcriptoma.
Investigar las caracteristicas del exoma y transcriptoma potencialmente subyacentes a la patogenia del varicocele (VE).
Estudio experimental y de cohortes.
Laboratorio de investigación académica y hospital afiliado a la universidad.
Once pacientes con VE cuyos padres también tenían VE, más 151 pacientes adicionales y 324 hombres sanos para las variantes genotípicas, para el modelo de ratón, ocho ratones macho Sprague-Dawley.
Se llevó a cargo la ligadura parcial de la vena renal para establecer modelos de ratón con los que realizar la secuenciación del RNA (RNA-seq) del transcriptoma completo.
Genes con expresión diferencial y/o refugio de distintas variantes patogénicas detectadas mediante RNA-seq y secuenciación del genoma complete (WES) se sometieron a un sondeo basado en la población para definir los genes candidatos a VE y fueron analizados mediante el ¨Gen ontology¨ y Kyoto Encyclopedia of Genes and Genomes¨ para identificar las vías involucradas en el VE.
La secuenciación de todo el RNA transcriptómico (RNA seq) se hizo utilizando cinco venas espermáticas izquierdas en modelos de ratón VE y en tres controles. Identificamos 9,688 genes y 18 vías mediante RNA-seq. y 160 genes albergando 270 variantes deletéreas y 16 vías mediante WES. Nueve genes (AAMP, KMT2D, IRS2, SPINT1, IFT122, MKI67, DCHS1, LAMA2 y CBL) tenían variantes en más de un paciente que se sometió a WES, y seis de esos genes (AAMP, SPINT1, MKI67, IFT122, LAMA2 y DCHS1) mostraban expresión diferencial. El sondeo basado en la población mostro que AAMP, SPINT1 y MKI67 estaban fuertemente relacionados con riesgo a sufrir VE. En total, dos conjuntos de datos omic 67 revelaron cuatro vías potencialmente relacionadas con VE.
Por primera vez, hemos descrito las características del exoma y transcriptoma del VE. La bi-ómica identificó nuevos genes candidatos y nuevas vías responsables de la incidencia y desarrollo del VE.
Whole Exome Sequencing Identifies a Rare Nonsense Mutation in FAM47C as a Possible Cause of Severe Oligospermia in Brothers With Varicocele
2019, Urology
Varicocele is a common cause of impaired semen parameters in men with infertility. Here, we investigated genetic variants as possible causes of varicocele with impaired semen parameters using whole exome sequencing in a family with 2 brothers with severe oligospermia, 1 unaffected brother, father, and the mother. Results showed a premature stop codon alteration on Chromosome X (37028866 CT) in the gene FAM47C. The affected brothers were found to be hemizygous for the variant, while the mother was a heterozygous carrier. In conclusion, identifying men with varicocele that would have impaired spermatogenesis, using approaches like whole-exome sequencing, can be paradigm shifting.
Varicocele management for infertility and pain: A systematic review
2018, Arab Journal of Urology
Citation Excerpt :
These anatomical findings may also correlate to a genetic component. A genetic study in 2005 examined first-degree relatives of men with a varicocele and found that 57% also had a clinically palpable varicocele, as compared to 7% in the control group [18]. Taken together, these data suggest a genetic and/or anatomical link underlying at least some of the biological consequences of having a varicocele.
Despite being first described two thousand years ago, the varicocele remains a controversial multifaceted disease process with numerous biological consequences including infertility, hypogonadism, and chronic orchidalgia. The underlying mechanisms remain poorly understood and likely include hypoxia, oxidative stress, hyperthermia, anatomical aberrations, and genetics as primary components. Despite a high prevalence amongst asymptomatic fertile men, varicoceles paradoxically also represent the most common correctable cause for male infertility. In this systematic review we discuss the rich historical aspects of the varicocele and the contemporary data regarding its clinical manifestations. We performed a systematic literature review with the goal of comparing outcomes and complication rates of each of the major surgical approaches as they relate to infertility and pain. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant systematic literature review for manuscripts focused on varicocele and its biological consequences. We identified 112 studies suitable for qualitative analysis and included 56 of these for quantitative analysis, with an emphasis on infertility and chronic pain outcomes. Taken together, the clinical work to date suggests that the highest fertility rates and the lowest complication rates are associated with the microsurgical subinguinal surgical approach to varicocelectomy. In all, 26–40% of patients undergoing varicocelectomy will successfully achieve short-term spontaneous pregnancy, and up to 90% of all patients undergoing varicocelectomy for pain will have improvement and/or resolution of their symptoms. Taken together, the data support an ongoing role for varicocelectomy in both of these clinical arenas.

View all citing articles on Scopus

View full text

Adult urologyInheritance of varicoceles

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Patient selection

Results

Comment

Conclusions

Acknowledgment

Fertil Steril

Urology

J Urol

J Urol

Fertil Steril

Fertil Steril

J Urol

Fertil Steril

Adult urology
Inheritance of varicoceles