The relationship between anogenital distance and the efficacy of varicocele repair
Michael L. Eisenberg, Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5118, USA. e-mail: firstname.lastname@example.org
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Anogenital distance (AGD) is a marker of genital development and adult testicular function. To date, there is no data on the clinical utility of using such an anthropomorphic variable.
About 30% of men will have no improvement in semen parameters after varicocele repair. It is currently difficult to assess which patients are most likely to benefit from surgical repair. The present study showed that men with a longer AGD had a higher likelihood of improvement after varicocelectomy. As such, AGD may allow clinicians to better counsel men on the efficacy of varicocele repair.
- • To investigate whether anogenital distance (AGD) can identify men most likely to show improved semen parameters after varicocele ligation, as AGD has been shown to correlate with intrinsic adult testicular function.
PATIENTS AND METHODS
- • Men with varicoceles who were evaluated at a men's reproductive health clinic in Houston were recruited.
- • AGD (the distance from the posterior aspect of the scrotum to the anal verge) was measured using digital callipers.
- • Logistic regression was used to compare outcomes after stratifying men based on AGD.
- • In all, 46 men with a mean (sd) age of 33.1 (6.3) years with postoperative semen data were recruited.
- • Semen concentration, motility, and total motile sperm count all showed significant improvement postoperatively (P < 0.01).
- • While 48% of men with a shorter AGD had improvements in sperm concentration postoperatively, 84% of men with a longer AGD improved (P= 0.01).
- • There was a trend toward a lower percentage of men (62% vs 84%) with shorter AGDs showing improvements in total motile sperm count (P= 0.09).
- • AGD may provide a novel metric to assess intrinsic testicular function and predict efficacy of varicocele repair.
A sexually dimorphic measure of genital development, anogenital distance (AGD) was initially used to sex animals [1–3]. Investigators have also used AGD to show that agents that disrupt androgen signalling in animal models can lead to abnormal genital lengths and even altered testicular function as measured by testosterone and sperm production [4–7]. Human studies have also linked AGD to adult testicular function, as assessed by testosterone and sperm production [8–10]. However, the clinical utility of such measurements remains unclear.
In clinical practice, most reports of varicocele-related testicular damage show persistent abnormalities of semen analysis parameters including concentration, motility, and/or morphology [11–15]. While many investigators have reported that treatment of varicocele improves semen parameters, pregnancy rates, and intrauterine insemination pregnancy and birth rates, a sub-set of men will not benefit after varicocelectomy. Indeed, it is estimated that semen parameters will improve in 60% of patients after varicocele repair . As AGD may provide a non-invasive method to assess male reproductive potential and testicular function, it may predict men with better inherent testicular function whose impaired semen parameters due to varicocele may be more likely to improve after varicocelectomy. Thus, we sought to determine if AGD was associated with improvement in semen parameters after varicocele repair.
PATIENTS AND METHODS
The methods of collection and cohort assembly have been previously reported . Briefly, after obtaining Institutional Review Board approval from Baylor College of Medicine, eligible patients were recruited from a urology clinic specialising in reproductive medicine from August 2010 to June 2011. Men with a history of orchidectomy, testicular torsion, previous malignancy, prior testosterone use, or prior chemotherapy exposure were excluded. In all, 59 men with genital measures underwent varicocele repair with follow-up semen analyses available for 46. All men provided written consent for participation.
The methods of genital measurement have been described previously. Briefly, in the supine, ‘frog-legged’ position with the legs abducted allowing the soles of the feet to meet, the distance from the posterior aspect of the scrotum to the anal verge was measured using a digital calliper (Neiko USA, Model No. 01407A). Given the age of the patients measured, the posterior scrotum was measured as the anterior border as it was felt to be a more comfortable, reliable, and reproducible measure. From the same position, the stretched penile length was measured from the base of the dorsal surface of the penis to the tip of the glans.
Testicular volume was estimated from the physical examination of one investigator (L.I.L.) at ≈25–27 °C.
All hormone assays were processed by a single, experienced laboratory (Laboratory for Male Reproductive Research and Testing, Baylor College of Medicine, Houston, TX, USA). Testosterone (normal range 200–1000 ng/dL), LH (normal range 6–19 mIU/mL), FSH (normal range 4–10 mIU/mL), and oestradiol (0.5–5 ng/dL) values were assessed using an automated, one-step competitive binding assay with the Beckman Coulter Access II Immunoassay system (Beckman Coulter, Inc., Brea, CA, USA). The assays were recalibrated daily with controls that spanned the normal range for all hormones.
anova was used to compare continuous variables and chi-squared analysis was used for categorical variables. For nonparametrically distributed variables (e.g. semen parameters), the Mann–Whitney or Wilcoxon rank-sum tests were used. Logistic regression was used to generate odds ratios (ORs) and 95% CIs. All P values were two-sided.
In all, 46 men underwent varicocelectomy who had follow-up data available (Table 1). Five men underwent a unilateral varicocelectomy and 41 men underwent a bilateral procedure. The mean (sd) age at varicocelectomy was 33.1 (6.3) years. Postoperative semen analyses were obtained at a mean of 6.3 months from varicocele ligation. In total, 67% of men had improvements in sperm density, 59% in sperm motility, and 73% of men in total motile sperm count after varicocele ligation. Overall, sperm density increased from a mean (sd) of 10.6 (2.4) to 12.2 (1.8) million sperm/mL (P < 0.01), sperm motility increased from 26.1 (18.2) to 33.9 (17.9)% (P < 0.01), and total motile sperm count increased from 9.0 (14.8) to 13.3 (15.1) million (P < 0.01).
Table 1. Demographic, anthropomorphic, and semen characteristics of cohort
| N ||21||25|| |
|Mean (sd):|| || || |
| Age at varicocele ligation, years||33.0 (7.4)||33.2 (5.4)||0.90|
| Height, cm||178.1 (7.1)||181.1 (8.6)||0.18|
| Weight, kg||96.6 (29.4)||96.7 (21.6)||0.99|
| BMI, kg/m2||30.4 (9.3)||29.4 (5.9)||0.65|
|Time of SA from varicocelectomy, months||7.0 (6.0)||5.8 (4.8)||0.44|
| N (%):|| || || |
| Laterality of varicocele:|| || ||0.50|
| Bilateral||18 (85.7)||23 (92)|| |
| Left||3 (14.3)||2 (8)|| |
| Grade of varicocele:|| || ||0.64|
| 1||3 (14.3)||2 (8.3)|| |
| 2||14 (66.7)||19 (79.2)|| |
| 3||4 (19.1)||3 (12.5)|| |
| Race|| || ||0.25|
| White||17 (81.0)||21 (84)|| |
| Black||2 (9.5)||4 (16)|| |
| Asian||2 (9.5)||0 (0)|| |
|Mean (sd):|| || || |
| SA volume, mL||2.8 (1.1)||2.6 (1.2)||0.58|
| SA concentration, million sperm/mL||12.4 (23.1)||9.0 (8.1)||0.77|
| SA motility, %||25.6 (18.5)||26.5 (18.4)||0.97|
| SA total motile count, ×106||9.7 (18.8)||8.4 (10.8)||0.82|
The mean (sd) AGD for men undergoing varicocelectomy was 31.3 (8.2) mm. In all, 21 (46%) men had an AGD of <30 mm and 25 (54%) had a longer AGD. There were no significant differences between preoperative semen parameters, age of men, or time from varicocelectomy until semen analysis between men with shorter or longer perineal lengths (Table 1).
When stratifying by AGD length (<30 vs ≥30 mm), a greater proportion of men with a longer AGDs showed improvements in total motile sperm count and sperm concentration after varicocelectomy than men with shorter AGDs (Table 2). In contrast, there were no significant differences in improvements in semen volume or sperm motility between men based on AGD length (Table 2).
Table 2. Improvement in semen quality after varicocele repair stratified by AGD length. Separate analyses were performed to examine any improvement, 10% improvement, 20% improvement, and 30% improvement in listed semen parameter. ORs and 95% CIs are listed representing the odds of improvement with an AGD of >30 mm
The present study showed that men with longer AGDs were more likely to have improvement in total motile sperm count and sperm concentration after varicocele repair. While no differences in preoperative characteristics existed between the AGD groups, perineal lengths were able to stratify the patients into those more likely to improve after repair. In infertile men with varicoceles, AGD may provide additional prognostic information about the likelihood of treatment success.
While generally regarded as efficacious, the treatment of varicoceles remains uncertain by some. In fact, the most recent Cochrane meta-analysis found no benefit to semen analysis when measuring pregnancy as an outcome . Unfortunately, trials that included men with subclinical varicoceles, as well as men with normal semen analyses, were included in treatment arms of analysed studies; despite current practice of discouraging treatment of such men. Marmar et al.  performed a systematic review of pregnancy outcomes after varicocele treatment but included only studies of men with palpable varicoceles and abnormal semen parameters. The authors found a significantly increased odds of pregnancy after varicocele treatment OR 2.87 (95% CI 1.33–6.20). It is important to note that the present patient population had clinical varicoceles and abnormal semen analyses before varicocele repair.
A sexually dimorphic measure, AGD appears to correlate with testicular function and development. Indeed, Hsieh et al.  showed shorter AGDs in boys with genital anomalies, i.e. hypospadias and cryptorchidism, establishing a link between normal genital development and perineal length in humans. Recent data has shown that AGD is also related to fatherhood, fertility and adult sperm production [8,9]. Thus, AGD may reflect the spermatogenic potential of the testis.
As a varicocele represents an acquired lesion that impairs testicular function, the AGD may provide information about the intrinsic function of the testis, thus helping to select men more likely to benefit from varicocele repair. It is important to note that even men with shorter AGDs still benefited from repair, as 62% of them showed an improved total motile sperm count after repair. Thus, regardless of AGD, most men will benefit from varicocele ligation. However, men with a longer AGD may have superior genital development and function, possibly explaining their higher likelihood of improvement after varicocelectomy. Thus, the present report establishes the clinical utility of AGD to help counsel patients on the efficacy of varicocele repair.
Certain limitations warrant mention. The number of men that underwent varicocelectomy in each of the AGD groups is relatively small. In addition, only men referred to and evaluated in our clinic were eligible for enrolment; therefore, it is possible that the present patient population does not represent all infertile men. Nevertheless, the present study represents the first clinical analysis of AGD suggesting that it may provide prognostic information in treatment outcomes of varicocelectomy.
CONFLICT OF INTEREST