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PubMed2006

The complex structure of the smooth muscle layer of spermatic veins and its potential role in the development of varicocele testis.

OBJECTIVES: Varicocele, a dilatation of the pampiniform venous plexus, is considered to cause male infertility. The exact mechanism of varicocele development is not clarified yet. This study focused on the structure of varicocele veins, compared with normal spermatic veins, and its potential role in varicocele development. METHODS: Morphologic and immunohistochemical studies using antibodies against vWF and neurofilament-200 (NF-200) were performed on spermatic vein fragments of 20 varicocele patients and 40 normal spermatic cords. Casting preparation of veins was performed on five normal spermatic cords. RESULTS: Casting preparation frequently revealed circular constrictions of normal spermatic vein lumina. Histologic evaluation showed a strong longitudinal smooth muscle layer in the adventitia of large veins in addition to the circularly organised tunica media. Serial sections showed smooth muscle fibres branching from the outer longitudinal into the inner circular layer. Immunostaining for vWF revealed high vascularisation of this outer layer. Interestingly, the number of nerve fibres marked by NF-200 immunostaining was considerably higher in large veins compared to the testicular artery. The longitudinal smooth muscle layer was significantly degraded in the presence of varicocele grades I and II, and did not even exist in varicocele grade III. Correspondingly, the number of vasa vasorum and nerve fibres was reduced in varicocele veins. CONCLUSIONS: Our data show a complex smooth muscle organisation of spermatic veins, which serves the basis for a contractile mechanism, providing an effective blood transport through pampiniform plexus. This mechanism is obviously damaged in the varicocele. Molecular processes behind this impairment remain to be clarified.

Adolescent↗
PubMed1987

Interrelationships of cigarette smoking, testicular varicoceles, and seminal fluid indexes.

Data on cigarette smoking, testicular varicoceles, seminal fluid indexes, and oligospermia were examined in 160 young men without known disease and in 94 husbands in infertile couples. The combination of smoking and testicular varicoceles is strongly related to the incidence of oligospermia, defined as sperm count less than or equal to 20 X 10(6)/ml, in each sample. Smokers with testicular varicoceles, in each sample, had a disproportionately high incidence of oligospermia. In the combined sample of 254 men, the smokers with testicular varicoceles had an incidence of oligospermia approximately ten times greater than that in nonsmokers with testicular varicoceles and approximately five times greater than that in men who smoked but were without testicular varicoceles. This relationship of cigarette smoking and testicular varicoceles to oligospermia has not been previously reported. The pathophysiologic basis of the interaction between smoking and varicoceles was theorized to be due to an increased secretion of catecholamines from the adrenal medulla, induced by cigarette smoking. The elevated catecholamine concentrations in the renal vein would then reach the testes via retrograde flow down the internal spermatic vein in men with testicular varicoceles, resulting in seminiferous tubule damage.

Adult↗
PubMed1987

What is the incidence of varicocele in a fertile population?

One hundred men with proven fertility who presented for vasectomy consultation were examined for testicular size and presence of a varicocele, including examination with the Doppler stethoscope for the presence of subclinical varicocele. A diagnosis of varicocele was established in 61%. In 17 patients, the varicocele was evident clinically, whereas in 44 patients it was subclinical (8 bilateral). There was a discrepancy in testicular size in 22 patients, but this group included 8 men without varicoceles and 7 with subclinical varicoceles. It is apparent that varicoceles, especially subclinical varicoceles, are an extremely common finding, even in a group of fertile men. The results suggest that subclinical varicoceles have no role in male infertility.

Adult↗
PubMed2006

Increased expression of hypoxia-inducible factor-1alpha in the internal spermatic vein of patients with varicocele.

PURPOSE: Varicocele is recognized as a cause of male infertility. Testis hypoxia may be one of the possible mechanisms of varicocele. We examined whether tissue hypoxia occurred in the ISV of patients with varicocele by detecting the expression of HIF-1alpha. MATERIALS AND METHODS: The study group consisted of 8 patients with grade 3 left varicocele. The control group consisted of 6 volunteers with left indirect inguinal hernia. Using a left inguinal surgical incision, a 1 cm section of ISV was resected from each patient in both groups as specimens for immunoblotting and immunohistochemical staining of HIF-1alpha. Results were analyzed using Student's t test. RESULTS: HIF-1alpha immunoblots from both groups revealed a single band. The relative intensity of the HIF-1alpha protein band was 10.92 +/- 2.70 in the control group and 73.15 +/- 8.93 in patients with varicocele (ie 7-fold higher). CONCLUSIONS: HIF-1alpha expression in the ISV of patients with varicocele was significantly higher than in the control group. This directly shows that hypoxia related pathophysiological changes have occurred in the ISV of patients with varicocele and that hypoxia may have also occurred in the testicular tissue. Thus, it would be of interest to investigate whether decreasing HIF-1alpha activation and testis hypoxia could reduce the recurrence of varicocele. To our knowledge, this is the first report on HIF-1alpha expression in human ISV. Additional studies will be necessary to clarify the relationship between testis hypoxia and male infertility in patients with varicocele.

Adult↗
PubMed1992

Intraoperative spermatic venography during varicocele surgery in adolescents.

Intraoperative internal spermatic venography performed immediately following varicocele ligation in the adolescent has been touted as reducing varicocele persistence rates. Previously published data corroborate this statement with low persistence rates. Other series in which venography was not performed report a failure rate of 9 to 30%. During a 5-year period a total of 64 varicocele ligations was performed in 62 male adolescents at our institution. Followup postoperatively revealed an overall varicocele persistence rate of 9%. All patients had intraoperative internal spermatic venography on the affected side. Of 64 venograms 16% had shown collateral drainage that, if not ligated, may have resulted in varicocele persistence. These cases accounted for only 1 of the persistent varicoceles. Additionally, venograms had demonstrated filling of the ipsilateral external iliac vein in 8% of the cases. Despite the fact that no attempt was made to ligate these collaterals, none of these patients had a persistent varicocele. After varicocele ligation 30 of 62 patients were followed long enough to evaluate for testicular catch up growth. Of these 30 patients 24 demonstrated an average relative increase in left testicular volume of 17%. These data support routine intraoperative internal spermatic venography while performing varicocele ligation in the adolescent.

Adolescent↗
PubMed2001

Management of prepubertal varicoceles-results of a questionnaire study among pediatric urologists and urologists with infertility training.

OBJECTIVES: Varicoceles are a common condition affecting male fertility seen by urologists. However, prepubertal varicoceles are much less common and their management is controversial. We designed a questionnaire to assess the practice patterns among urologists (pediatric urologists/urologists with infertility training) with regard to prepubertal varicocele management. METHODS: A 15-point questionnaire pertaining to management issues of prepubertal varicoceles was sent to 150 pediatric urologists and 150 urologists with infertility training. Two clinical scenarios referring to treatment algorithms of prepubertal varicoceles were included. RESULTS: Of the 300 questionnaires mailed, 174 urologists (58%) responded. Seventy-five of the respondents were urologists with an interest in infertility, and 99 were pediatric urologists. Of the 174 respondents, 86.2% treated prepubertal varicoceles and 13.8% referred patients to interventional radiologists for embolization. The ratio of varicocelectomy to expectant management was about equal between urologists with infertility training and pediatric urologists (46% versus 54%). A difference in testicular size was the most common indication for varicocelectomy (80.5%), followed by pain (51.1%) and potential fertility problems (24.7%). About one third of all urologists would perform varicocelectomy on patients of any age and seven (4%) would not operate before puberty. In 136 responses (78.2%), follow-up information was not available. Among the 35 respondents with follow-up information (21.8%), 21 reported infertility occurring after varicocelectomy and 16 after expectant management. If varicocelectomy was performed, most urologists (47.2%) used magnification loupes, 29.3% used microscopes, and 29% used no magnification. The preferred approach was inguinal (Ivanissevich) in 35.6% followed by subinguinal in 30%; 21% performed retroperitoneal varicocelectomy (Palomo) and 9.8% used a laparoscopic approach. Of the 300 complications reported, postoperative hydroceles were the most common (40.4%), followed by recurrence (20.8%) and hematomas (17.4%). CONCLUSIONS: The management of prepubertal varicoceles is controversial among different urologic subspecialties (pediatric urology/infertility). Differences include indications, timing, and techniques used for varicocelectomy. Accurate follow-up information for children with prepubertal varicoceles is rare. A prospective randomized study comparing varicocelectomy versus expectant management of prepubertal varicoceles is needed to assess the outcomes and define uniform treatment criteria.

Adolescent↗
PubMed1997

Prepubertal varicoceles.

OBJECTIVES: Varicoceles are rarely detected in prepubertal boys. In an effort to further determine the natural history of prepubertal varicoceles, we have reviewed our experience with prepubertal boys who had varicoceles. METHODS: Eleven patients with prepubertal varicoceles were seen. The majority of patients (9 of 11) were asymptomatic. The mean age was 10.8 years (range 6 to 12). Ten of 11 patients had left-sided varicoceles. All varicoceles were grade III except for one that was grade II. Four patients underwent varicocele ligation, 3 via the Ivanessevich approach and 1 via the Palomo approach. RESULTS: The 4 patients who underwent varicocele ligation (operative group) had a follow-up that ranged from 6 to 72 months (mean 27.2) and the 7 patients who were observed (nonoperative group) had follow-up that ranged from 17 to 84 months (mean 40.8). All patients in the operative group exhibited "catch-up" growth of the affected testicle (mean relative testicular size 47% to 84% at follow-up). The relative left testicular size in the nonoperative group had decreased by a mean of 16.8% from the time of presentation (100% to 83.2% on follow-up). CONCLUSIONS: We conclude that prepubertal boys should be screened in the standing position for the presence of varicoceles. Secondary causes should be excluded. Patients may ultimately require intervention as our initial experience suggests improved testicular growth with early surgical repair.

Age Factors↗
PubMed1997

Color Doppler ultrasound criteria to diagnose varicoceles: correlation of a new scoring system with physical examination.

OBJECTIVES: Color Doppler ultrasound (CDU) diagnostic criteria for varicoceles are poorly defined, and the role of CDU in diagnosing varicoceles is controversial. The purpose of this study is to assess the diagnostic accuracy of CDU for varicoceles compared to physical examination. METHODS: We prospectively studied 64 patients with CDU and collected the following data: maximum diameter of scrotal veins, the presence of a venous plexus, sum of the diameter of up to six veins of the plexus, and the duration and amplitude of flow change on Valsalva maneuver. To avoid interphysician variation, all patients were examined by one designated senior urologist with the sonographer remaining unaware of the findings. RESULTS: CDU parameters of 127 testis units in 64 patients were analyzed and compared to the physical findings. Fifty-nine testis units were positive and 57 units were negative for varicocele on physical examination. In 11 testis units, results of physical examination were inconclusive regarding the presence of varicocele. The commonly accepted CDU criterion for varicocele (maximal vein diameter of 3 mm or greater) had a sensitivity of 53% and specificity of 91% compared to physical examination. We developed a new scoring system incorporating the maximal venous diameter (score 0 to 3), the presence of a venous plexus and the sum of the diameters of veins in the plexus (score 0 to 3), and the change of flow on Valsalva maneuver (score 0 to 3). Using a total score of 4 or more to define the presence of CDU-positive varicocele, we observed a sensitivity of 93% and a specificity of 85% when compared to physical examination. All moderate to large varicoceles found on physical examination were positive by CDU diagnosis using the scoring system, but the same group had only a 68% positive rate by traditional CDU diagnostic criteria. CONCLUSIONS: Using the proposed new scoring system, CDU has been shown to be a reliable and accurate method of diagnosis for varicoceles compared to the current reference standard physical examination. CDU has the advantages of being able to objectively examine venous plexus and measure blood flow parameters and to be less observer-dependent than physical examination.

Adult↗
PubMed2002

Recurrent varicocele: role of antegrade sclerotherapy as first choice treatment.

OBJECTIVE: To underline the role of antegrade sclerotherapy as first choice treatment in recurrent varicocele. METHODS: In 53 patients, aged 11-38 years, observed over a 30-month period, antegrade sclerotherapy was carried out for the treatment of recurrent varicocele. In seven of these patients, varicocele was bilateral. The right varicocele, however, had not been previously detected and these patients were, therefore, submitted to simultaneous bilateral antegrade sclerotherapy. RESULTS: Antegrade sclerotherapy was feasible in all 53 patients (60 varicoceles) and no significant complications were observed. Unsuccessful results occurred in only two out of the 55 varicoceles observed over a minimum follow-up period of six months. CONCLUSIONS: Whilst antegrade sclerotherapy is recognized as a low-cost, safe and effective method in the management of varicocele, the success rate in recurrent varicocele is even greater than in primary varicocele. If, in the preceding treatment, the internal spermatic vein has presumably been occluded (percutaneous retrograde sclerotherapy, surgical or laparoscopic retroperitoneal ligation of the entire bundle), antegrade sclerotherapy should be considered the treatment of choice.

Adolescent↗
PubMed2003

High prevalence of bilateral varicoceles confirmed with ultrasonography.

OBJECTIVE: To determine the incidence of bilateral varicoceles in men presenting to a single infertility clinic. SUBJECTS AND METHODS: From March 1999 to March 2000, 60 men presenting with an inability to initiate pregnancy (consecutive and unselected), were determined by clinical exam to have varicoceles. These men were sent for color Doppler ultrasound to evaluate the incidence of varicocele bilaterality. Two men with a solitary testis were excluded from the study. RESULTS: Of the 58 men, 45 (77.5%) had ultrasound verified bilateral varicoceles. In the 13 remaining patients, 8 (13.8%) had a unilateral left varicocele, 4 (6.9%) had no varicoceles demonstrated by ultrasound, and a single patient (1.7%) was reported to have a unilateral right varicocele. CONCLUSIONS: Routine scrotal ultrasound provides valuable information in the diagnostic evaluation of infertile men. Based on advancements in diagnostic techniques, investigators have recently observed that the incidence of bilateral varicoceles to be significantly greater than the previously reported. Our study demonstrated the incidence of bilaterality in infertile men to be a substantial 77.5%. An overlooked right varicocele (whether subclinical or not) may be detrimental to future fertility and needs further investigation.

Adult↗
PubMed2001

Laparoscopic treatment of varicoceles in children. Multicentric prospective study of 90 cases.

PURPOSE: The aim of this study was to assess the results of the laparoscopic treatment of varicoceles. MATERIAL AND METHODS: 92 observations were received, however 5 patients underwent a simultaneous associated open surgery; 90 varicoceles were evaluated (3 bilateral varicoceles). The dilated spermatic veins were treated by clips and partial resection in 74.7 %, by coagulation and partial resection in 21 %, and by clips in 4.3 %. The spermatic artery was ligated in 60 varicoceles and preserved in 28; in 2 cases it was not specified. The results were studied with a mean follow-up of 11.1 months (2 to 36 months). RESULTS: The varicocele disappeared in 76 cases (84.4 %) and diminished significantly in 12 cases (13.2 %) where it was large before treatment. Two middle-sized varicoceles were not modified by the treatment. Therefore, the results must be considered good or excellent in 97.6 % of cases. The spermatic artery was preserved in 28 cases and the size of the varicocele was not good in 9 (32.1 %); it was ligated in 60 cases and the size of the varicocele was not good in 5 cases (8.4 %) -- p < 0.01. In 42 cases the testicular size was noted before and after treatment, and likewise the conservation or not of the spermatic artery; the 30 artery ligations produced no testicular atrophy; only 3 hypotrophic testes were noted with a loss of size of between 8.4 and 59 % with regard to the contralateral testis. In 27 cases, the testicular size remained normal or increased if it was hypotrophic before treatment; there was a good result in 90 % of cases with no atrophy. When the spermatic artery was preserved (12 cases), 1 hypotrophy occurred with a loss of size of 16.7 % -- NS. CONCLUSION: The laparoscopic treatment of varicoceles is an efficient technique and the complete ligation of the whole vascular spermatic pedicle above the vas deferens offers excellent success, without atrophy.

Adolescent↗
PubMedDate not supplied

Varicocele in schoolboys.

This study was conducted to examine the effect of height and weight on the incidence of varicocele in schoolboys aged 5-16 years and the impact of varicocele on testicular size. Genital stage, height, weight, varicocele grade, and testicular size were recorded for 3047 school boys who were clinically examined while standing by a specialist in urology. Left varicocele was detected in 98 of the boys who were all aged 9-16 years. The mean weight of boys with and without varicocele was 42 kg (95% confidence interval [CI] 40-44 kg) and 47 (95% CI 47-47 kg), respectively (p =.00). There was no difference in mean height between the two groups nor in left and right testicular volume. Although 6 boys with varicocele had a left testicular volume > or =2 mL less than right, there were also 7 boys of comparable age who had a left testicular volume > or =2 mL larger than right. The incidence of varicocele in Greek adolescents is low. Boys with varicocele weighed significantly less but there were no significant differences in height or left versus right testicular volumes. In the light of these observations, the use of left testicular hypotrophy (> or =2 mL compared with the right testicle) should be reconsidered as an indicator for varicocele-induced damage of the testicle in this age group.

Adolescent↗
PubMedDate not supplied

Effects of varicocele on male fertility.

Varicoceles are vascular lesions of the pampiniform plexus and are the most common identifiable abnormality found in men being evaluated for infertility. Despite the long history associated with varicoceles, there remains much controversy regarding their diagnosis and management. The purpose of this manuscript is to address three of the most pressing controversies: (i) the association of varicoceles with male infertility, (ii) whether varicoceles exert a progressive deleterious effect and (iii) the relationship of varicocele size and outcome following varicocele repair. The current literature is reviewed in an effort to answer these questions. Based upon this analysis, conclusions can be drawn regarding the best management of varicoceles in subfertile men, adolescents, young fertile men and men with subclinical varicoceles. Although there remain many controversies due to a paucity of data, there appears to be a significant difference between adults and adolescents with respect to a progressive deterioration of semen parameters and it is clear that subclinical varicoceles do not play a major role in male infertility.

Adolescent↗
PubMedDate not supplied

Varicocele--the most common cause of male factor infertility?

Varicocele is often cited as the most common cause of male factor infertility. Arguments in support of this statement include reports of increased prevalence of varicocele in populations of infertile men compared with fertile or otherwise unselected men, association of varicocele with abnormal semen parameters, and improvements in semen parameters and/or pregnancy rates after varicocele repair. Logically, there would appear to be three possibilities regarding the relationship between varicocele and fertility: (i) varicocele has no association with or effect on male fertility; (ii) varicocele may be associated with, but is not the cause of, male subfertility; and (iii) varicocele is a direct cause of male subfertility. In the following, we review evidence from the literature for and against these three possibilities: at the current time, available evidence appears inadequate to confirm or deny any of these three possibilities. Since the ultimate goal of infertile couples is to conceive, it seem logical that future varicocele research should focus primarily on adequately powered, controlled clinical trials in well-characterized infertile couples, randomized to intervention or appropriate controlled observation, with pregnancy as the primary outcome.

Humans↗
PubMed1999

Comparison of bilateral versus unilateral varicocelectomy in men with palpable bilateral varicoceles.

PURPOSE: The left varicocele is usually larger in men with bilateral varicoceles. We hypothesized that most of the benefit of varicocelectomy would derive from repair of the larger varicocele. To test this hypothesis we prospectively compared the effect of unilateral versus bilateral microsurgical varicocelectomy in men with large (grade III) or moderate (II) left varicocele associated with small but palpable (I) right varicocele. MATERIALS AND METHODS: A total of 91 patients were prospectively followed and included in the study. Of the patients 65 underwent bilateral and 26 underwent unilateral left repair. All patients underwent preoperative and postoperative semen analysis. RESULTS: Motile sperm concentration increased from 12.1+/-1.7 to 23.7+/-31.8 (95.8% change) in the bilateral group compared with an increase from 19.5+/-21.4 to 27.8+/-34.8 (42.6% change) in the unilateral group (p<0.05). Similarly, sperm concentration increased from 23.8+/-29.5 to 48.6+/-61.3 (157.6% change) in the bilateral group compared with an increase from 41.1+/-40.9 to 59.5+/-66.7 (44.8% change) in the unilateral group (p<0.05). CONCLUSIONS: Bilateral varicocelectomy resulted in significantly greater improvement in post-operative seminal parameters than unilateral repair in patients with grades II to III left varicocele associated with grade I right varicocele. Even a small, unrepaired palpable right varicocele continues to have a detrimental effect on bilateral testis function. Men with bilateral palpable varicoceles require bilateral repair.

Adult↗
PubMed2004

The adolescent varicocele: diagnostic and treatment patterns of pediatricians. A public health concern?

PURPOSE: We determine whether practice patterns of pediatricians contribute to delays in diagnosing and treating adolescents with varicoceles. MATERIALS AND METHODS: A survey consisting of 11 multiple-choice questions was mailed to 5,000 pediatricians selected by zip code in New York State. Zip codes were chosen to reflect urban, suburban and rural counties. RESULTS: A total of 544 of the 5000 (10.9%) surveys were returned, and 92 (16.9%) pediatricians acknowledged that they did not routinely perform physical examinations of the genitalia of adolescent males patients. Of 497 pediatricians who routinely or occasionally examine the genitalia 54 (10.9%) did not examine for the presence of varicoceles. When pediatricians were asked how they assess for the presence of varicoceles, 13 of 521 (2.5%) only used visual inspection, 50 (9.6%) only examined patients in the supine position and 379 (72.7%) of these pediatricians never used Valsalva maneuvers. Of 517 respondents 442 (85.5%) referred patients with varicoceles to a urologist for followup and 72 (13.9%) did no further evaluation. When asked to indicate what they thought was the greatest concern regarding the pediatric varicocele, 327 of 497 (65.0%) pediatricians indicated deterioration of future infertility, 120 (30.0%) indicated testicular growth retardation, 105 (24.2%) indicated pain and 18 (4.3%) indicated cosmesis. CONCLUSIONS: A significant percentage of pediatricians do not routinely perform physical examinations for varicoceles or appropriately examine for varicoceles, despite the majority being aware of the potential significance of varicoceles. This study demonstrates the need for increased educational efforts among pediatricians regarding the need for physical examination of the genitalia, the techniques for appropriate physical examination, and the need for appropriate referral and followup of adolescents with varicoceles.

Adolescent↗
PubMed2004

The role of reactive oxygen species and apoptosis in the pathogenesis of varicocele in a rat model and efficiency of vitamin E treatment.

We investigated role of reactive oxygen species (ROS) and apoptosis in the pathogenesis of infertility in experimental model of varicocele. The protective effect of vitamin E was also examined. Three groups of rats were constructed as the first group had sham operation, experimental varicoceles were established by partial ligation of the left renal vein in later two groups. Third group had received vitamin E. Production of ROS was determined by chemiluminescence assay (CL). The in situ end labelling technique was utilized to investigate apoptosis. Tissue vitamin E levels were measured by high performance liquid chromatography. The differences between luminol enhanced CL levels of groups were not statistically significant. However, the difference between CL levels of lucigenin probe in left testicles of sham and varicocele groups were statistically significant ( p = 0.0007). Similarly, the results of the third group receiving vitamin E significantly differed from the varicocele group ( p = 0.0025). The difference of apoptotic index was also statistically significant between sham and varicocele groups ( p = 0.0038). Although the values of apoptotic index detected in the vitamin E group were lower compared with the varicocele group, the difference was not significant. This study proposes that ROS production and apoptosis in the testicles were induced with experimental varicocele. Vitamin E had a protective role. An increased rate of apoptosis with experimental varicocele suggests a molecular alteration, which may involve ROS overproduction as the triggering mechanism. Consequently, this study indicates an association between varicocele and infertility at molecular level through stimulation of ROS and apoptosis.

Animals↗
PubMed1990

The effect of post-pubertal varicocele on testicular volume.

Paediatric varicocele is a well known entity but its effect on adult infertility has not been adequately clarified. Since measurement of testicular volume is currently the best method of estimating the male reproductive potential, 945 boys aged between 13 and 18 years were examined with regard to testicular volume and the incidence of varicocele. The average volumes for right and left testes were 15.087 +/- 0.237 and 14.514 +/- 0.347 ml respectively, and the incidence of varicocele was 16.7%. The incidence increased from 14.5 to 21.7% as the ages increased from 14 to 18. The differences in volume of the 2 testes in boys with varicocele were statistically significant when compared with the normal group, but this significance failed to become more pronounced when the slight varicocele group (grade I) was included with the normal group and compared with the severe varicocele group (grades II and III). There may be no significant differences between the volumes of the 2 testes in boys with varicocele when careful measurement and strict statistical analyses are applied. However, some boys in the varicocele group were found to have testicular volumes below the confidence interval (mean - SE) or under 1 SD, and the 2 testicular volumes differed in certain age groups. This group requires further follow-up. The results of this study have added further contradictory findings to the issue of paediatric varicocele in terms of testicular atrophy, estimation of potential fertility and the indications for immediate surgery. There is a need for further prospective controlled trials.

Adolescent↗