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ORIGINAL ARTICLE
Year : 2018  |  Volume : 45  |  Issue : 2  |  Page : 72-75

Anogenital distance in males attending assisted reproduction center


1 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus; Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India
2 Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India
3 Department of Biotechnology and Microbiology, Karnatak University, Dharwad, Karnataka, India
4 Department of Biochemistry, Kuvempu University, Shankarghatta, Shivamogga, Karnataka, India

Date of Web Publication10-Dec-2018

Correspondence Address:
R B Nerli
Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus, Belagavi - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jss.JSS_34_18

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  Abstract 


Introduction: Anogenital distance (AGD) is a marker for endocrine disruption in animal studies in which decreased distance has been associated with testicular dysfunction. Measurement of AGD has also been used as a marker for genital development. Recently, it has been used to correlate with sperm production. In this study, we have investigated the relationship between AGD, sperm parameters, testicular size, and total testosterone levels in men attending assisted reproduction center (ARC). Materials and Methods: All the male partners of infertile couples presenting to the ARC were prospectively included in the study. Semen analysis, serum and blood biochemistry tests, and hormone assessment were done in all patients. The AGD measurements were done with the patient lying in supine position, and the distance from the posterior aspect of the scrotum to the anal verge was measured using a digital caliper. Results: The mean AGD was 3.19 ± 0.18 cm in patients with azoospermia, 3.40 ± 0.28 in oligospermia, 3.38 ± 0.24 in oligoasthenospermia, 3.30 ± 0.21 in oligoasthenoteratospermia, and 4.21 ± 0.23 in patients with normal sperm parameters. The testicular volume was significantly lower in patients with abnormal sperm parameters when compared to patients with normal sperm parameters. The total testosterone levels were significantly lower in patients with abnormal sperm parameters when compared to patients with normal sperm parameters. Conclusions: AGD may provide a novel metric to assess testicular function in men. A longer AGD is associated with fatherhood and may predict normal male reproductive potential.

Keywords: Genitalia, hormones, perineum, semen analysis, testicular size, testosterone


How to cite this article:
Nerli R B, Ghagane SC, Hiremath MB, Dixit NS, Neelagund S. Anogenital distance in males attending assisted reproduction center. J Sci Soc 2018;45:72-5

How to cite this URL:
Nerli R B, Ghagane SC, Hiremath MB, Dixit NS, Neelagund S. Anogenital distance in males attending assisted reproduction center. J Sci Soc [serial online] 2018 [cited 2019 Mar 19];45:72-5. Available from: http://www.jscisociety.com/text.asp?2018/45/2/72/247153




  Introduction Top


Anogenital distance (AGD) is a sexually dimorphic measurement and was initially used to identify the sex/gender in animals.[1],[2] Several studies done recently have shown that boys have a greater perineal length than girls.[3],[4],[5] Similarly, AGD has been used by several investigators to show that agents which disrupt androgen signaling in animal models can lead to abnormal genital length and even altered testicular function as measured by testosterone and sperm production.[6],[7],[8] Recently, a study done on healthy male volunteers demonstrated a positive relationship between AGD and semen concentration, motility, and morphology.[9] Eisenberg et al. reported that fertile men had greater anogenital length compared to infertile men.[10] Assuming that AGD is determined in utero, these studies suggest that possible in utero influences may have had an impact on genital development and adult testicular function.

The AGD has been shown to vary based on the integrity of androgen pathways, and it is possible that a shorter AGD may signal impaired testicular function in men.[10] Indeed, rodent studies have established critical gestational windows where genital development (i.e., penile length [PL], AGD, and testis weight) can be irreparably altered by exposure to endocrine disruptors. Eisenberg et al.[10] did a cross-sectional study of 117 consecutive men being evaluated for infertility and 56 men with proven fertility recruited from an andrology clinic. The infertile men possessed significantly shorter mean AGD and PL compared to the fertile controls (AGD: 31.8 vs. 44.6 mm and PL: 107.1 vs. 119.5 mm, P < 0.01). The difference in AGD persisted even after accounting for ethnic and anthropomorphic differences. In addition to fatherhood, on both unadjusted and adjusted linear regressions, AGD significantly correlated with sperm density and total motile sperm count. After adjusting for demographic and reproductive variables, for each 1 cm increase in a man's AGD, the sperm density increased by 4.3 million sperm per mL (95% confidential interval [CI]: 0.53–8.09, P = 0.03) and the total motile sperm count increased by 6 million sperm (95% CI: 1.34–10.58, P = 0.01). On adjusted analyses, no correlation was seen between PL and semen parameters. We took up this study to assess the AGD in male patients attending the assisted reproduction center (ARC) of our hospital and compared its relationship to the sperm count.


  Materials and Methods Top


After obtaining institutional/university ethical board approval, all the male partners of infertile couples presenting to the ARC were prospectively included in the study. The age of the male partner, history of infertility, and physical examination findings were noted in all. Semen analysis, serum and blood biochemistry tests, and hormone assessment were done in all patients.

Anogenital distance measurements

The AGD measurements were done with the patient lying supine and in 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 caliper (Swastik Scientific Instruments Private Limited, Thane, Mumbai, Maharashtra, India) [Figure 1]. The soles of the feet were between 12 and 18 inches from the buttocks for all measurements. The anal verge was marked as the anteriormost point where the anus begins. The posterior aspect of the scrotum was the point where the rugated scrotal skin meets the perineum. 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.
Figure 1: (a) Digital vernier caliper. (b) Anogenital distance as measured with men in supine, frog-leg position

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Semen analysis

As part of our departmental practice, all patients were evaluated for infertility with at least two semen analyses performed. Using the WHO guidelines, semen analyses were performed manually on all patients evaluated for infertility within 1 h of collection. The volume, density (million per mL), and motility were recorded. Volume, percentage motility, and density were multiplied to determine the total motile sperm count.

Statistical analysis

Unpaired t-tests were used to evaluate the association between categorical variables.


  Results Top


During the study from January 2012 to December 2016, a total of 277 infertile/subfertile couples were referred to the ARC of our hospital for evaluation and further management using assisted reproduction techniques. The mean age of the male partners of the infertile couple was 35.96 ± 8.53 years. Semen analysis revealed 27 (9.74%) patients to have azoospermia, 91 (32.85%) oligospermia, 26 (9.38%) oligoasthenospermia, 76 (27.43%) oligoasthenoteratospermia, and 57 (20.57%) normal sperm parameters. The mean AGD was 3.19 ± 0.18 cm in patients with azoospermia, 3.40 ± 0.28 in oligospermia, 3.38 ± 0.24 in oligoasthenospermia, 3.30 ± 0.21 in oligoasthenoteratospermia, and 4.21 ± 0.23 in patients with normal sperm parameters. The AGD was significantly shorter in males with abnormal sperm parameters as compared to males with normal sperm parameters [Table 1].
Table 1: Semen and testicular volume analysis of the patients

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The mean testicular volume was 11.59 ± 3.18 cc, 13.49 ± 2.99 cc, 13.07 ± 3.74 cc, 13.21 ± 3.91 cc, and 17.96 ± 3.77 cc in patients with azoospermia, oligospermia, oligoasthenospermia, oligoasthenoteratospermia, and normal sperm parameters, respectively. The testicular volume was significantly lower in patients with abnormal sperm parameters when compared to patients with normal sperm parameters. The mean total testosterone values were 220.44 ± 19.93, 276.14 ± 37.22, 272.26 ± 33.15, 274.81 ± 45.11, and 447.24 ± 147.26 in patients with azoospermia, oligospermia (<15 mill./ml), oligoasthenospermia (<20 × 106/mL), oligoasthenoteratospermia, and normal sperm parameters, respectively. The total testosterone levels were significantly lower in patients with abnormal sperm parameters when compared to patients with normal sperm parameters.


  Discussion Top


Our study clearly demonstrates an association between AGD and serum testosterone levels in a cohort of adult men who were part of the infertile/subfertile couples being evaluated in an ARC. In addition, there was a definite relationship between AGD and testicular volume and similarly between AGD and semen analysis. Mendiola et al.[9] examined associations between AGD and semen parameters in 126 adult males and reported that there was a strong correlation between AGD and all semen parameters. The authors concluded that the androgenic environment during early fetal life exerted a fundamental influence on both AGD and adult sperm counts in humans, similar to those demonstrated in rodents.

Of the four hormones (i.e., testosterone, estrogen, luteinizing hormone, and follicle-stimulating hormone) which are routinely assessed in an infertile male, it is only testosterone that is synthesized in the testis. Thus, it is perhaps not surprising that a relationship with genital distance has been only found for testosterone. Our study clearly shows this relationship. Eisenberg et al.[10] were the first to report an association between perineal length and androgen levels in men. They believe that AGD may predict normal genital development in men and, therefore, could provide a novel metric to assess testicular function. They also believe that if AGD at birth predicted adult AGD, then serum testosterone levels in adulthood would depend on factors operating in the fetal period.

Fetal programming of later disease risk has been well established in metabolic syndrome.[11],[12],[13] Fetal programming of common male reproductive disorders has formed the basis for the testicular dysgenesis syndrome (TDS) hypothesis,[14] which proposes that faulty differentiation of fetal testis somatic cells results in suboptimal function, leading to later development of one or more reproductive disorders. However, testing of this hypothesis in males, especially for conditions that emerge in young adulthood (e.g., low sperm counts), has been impossible because there has been no means of “seeing back in time” to identify whether fetal testis dysfunction had occurred in that person.[15] Animal model studies [16],[17] have identified that AGD may provide the means for retrospectively determining fetal androgen exposure during masculinization; AGD is approximately twice as long in male rats as in females.[17]

Eisenberg et al.[10] clearly demonstrated an association between AGD and fatherhood in a cohort of U.S. adult men evaluated in an andrology practice. They also reported that the AGD positively correlated with a man's fertility potential as assessed by sperm production. They also reported that the genital measurements were closely related to fatherhood. This was also seen in our study. The size of the testis was significantly smaller in males with abnormal sperm parameters when compared to males with normal parameters.

In human studies in infants, it has been well established that the AGD is longer in boys as compared to girls. This has led investigators to use AGD as a marker for normal genital development. Hsieh et al.[1] demonstrated shorter AGDs in boys with genital anomalies (i.e., hypospadias and cryptorchidism), establishing a link between normal genital development and perineal length in humans. A study of Caucasian infants (42 controls and 77 with hypospadias) reported a significant reduction (P = 0.002) in AGD in boys with hypospadias.[1] Similar studies reported a more modest reduction in AGD in boys with cryptorchidism (P = 0.02).[1],[18]

As of now, AGD measurement has been used primarily as a clinical research tool to gain better insight into the developmental origin of male reproductive disorders, TDS in particular, to establish the importance of fetal androgen exposure in determining these disorders, but also the variation in reproductive parameters (testis and penis size and sperm count) within the normal population. AGD measurement offers the possibility of gaining functional insight into the hidden process of fetal androgen exposure (masculinization programming window) as this critical period is inaccessible for the study. Once better understanding is in place, then applying AGD measurement in clinical situations would be useful. As of now, such applications must be considered speculative and could include (1) measurement of AGD before puberty to forecast later reproductive function, (2) evaluation of whether fetal exposure to endocrine disruptors can adversely affect male reproductive development in humans, as it does experimentally in rodent studies, and (3) measurement of AGD in newborns (with micropenis) at birth could provide an indicator of what PL could be potentially achievable with sufficient androgen exposure/treatment.[13]


  Conclusions Top


Our study helps in establishing a relationship between AGD and testicular function in adults. Testicular size and AGD correctly predicted sperm production in our cohort of males.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hsieh MH, Breyer BN, Eisenberg ML, Baskin LS. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr Urol Rep 2008;9:137-42.  Back to cited text no. 1
    
2.
Greenham LW, Greenham V. Sexing mouse pups. Lab Anim 1977;11:181-4.  Back to cited text no. 2
    
3.
Thankamony A, Ong KK, Dunger DB, Acerini CL, Hughes IA. Anogenital distance from birth to 2 years: A population study. Environ Health Perspect 2009;117:1786-90.  Back to cited text no. 3
    
4.
Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M. Anogenital distance in human male and female newborns: A descriptive, cross-sectional study. Environ Health 2004;3:8.  Back to cited text no. 4
    
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Sathyanarayana S, Beard L, Zhou C, Grady R. Measurement and correlates of ano-genital distance in healthy, newborn infants. Int J Androl 2010;33:317-23.  Back to cited text no. 5
    
6.
Scott HM, Hutchison GR, Jobling MS, McKinnell C, Drake AJ, Sharpe RM, et al. Relationship between androgen action in the “male programming window,” fetal sertoli cell number, and adult testis size in the rat. Endocrinology 2008;149:5280-7.  Back to cited text no. 6
    
7.
Foster PM, Mylchreest E, Gaido KW, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum Reprod Update 2001;7:231-5.  Back to cited text no. 7
    
8.
Cowin PA, Gold E, Aleksova J, O'Bryan MK, Foster PM, Scott HS, et al. Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism. Endocrinology 2010;151:783-92.  Back to cited text no. 8
    
9.
Mendiola J, Stahlhut RW, Jørgensen N, Liu F, Swan SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect 2011;119:958-63.  Back to cited text no. 9
    
10.
Eisenberg ML, Hsieh MH, Walters RC, Krasnow R, Lipshultz LI. The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS One 2011;6:e18973.  Back to cited text no. 10
    
11.
Macleod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, et al. Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 2010;33:279-87.  Back to cited text no. 11
    
12.
Welsh M, MacLeod DJ, Walker M, Smith LB, Sharpe RM. Critical androgen-sensitive periods of rat penis and clitoris development. Int J Androl 2010;33:e144-52.  Back to cited text no. 12
    
13.
Dean A, Sharpe RM. Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: Relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 2013;98:2230-8.  Back to cited text no. 13
    
14.
Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972-8.  Back to cited text no. 14
    
15.
Sharpe RM, Skakkebaek NE. Testicular dysgenesis syndrome: Mechanistic insights and potential new downstream effects. Fertil Steril 2008;89:e33-8.  Back to cited text no. 15
    
16.
Wolf C Jr., Lambright C, Mann P, Price M, Cooper RL, Ostby J, et al. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p, p'-DDE, and ketoconazole) and toxic substances (dibutyl – And diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol Ind Health 1999;15:94-118.  Back to cited text no. 16
    
17.
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008;118:1479-90.  Back to cited text no. 17
    
18.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056-61.  Back to cited text no. 18
    


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