Development of the Penis During the Human Fetal Period (13 to 36 Weeks After Conception)

Development of the Penis during the Human Fetal Period (13 to 36 Weeks after Conception)

Carla B. M. Gallo, Waldemar S. Costa, Angelica Furriel, Ana L. Bastos and Francisco J. B. Sampaio*

From the Urogenital Research Unit, State University of Rio de Janeiro, Rio de Janeiro, Brazil

Purpose: We analyzed the development of the area of the penis and erectile Abbreviations structures (corpora cavernosa and corpus spongiosum) and the thickness of the and Acronyms tunica albuginea during the fetal period (13 to 36 weeks after conception) in ¼ MRI magnetic resonance humans to establish normative patterns of growth. imaging Materials and Methods: We studied 56 male human fetuses at 13 to 36 weeks WPC ¼ week post conception after conception. We used histochemical and morphometric techniques to analyze the parameters of total penile area, area of corpora cavernosa, area of Accepted for publication May 20, 2013. Study received institutional ethical commit- corpus spongiosum, and thickness of tunica albuginea in the dorsal and ventral tee approval. regions using ImageJ software (National Institutes of Health, Bethesda, Supported by grants from the National Maryland). Council of Scientific and Technological Develop- ment (CNPq-Brazil) and the Foundation for Results: Between 13 and 36 weeks after conception the area of the penis varies Research Support of Rio de Janeiro (FAPERJ). from 0.95 to 24.25 mm2. The area of the corpora cavernosa varies from 0.28 to * Correspondence: Urogenital Research Unit, 9.12 mm2, and the area of the corpus spongiosum varies from 0.14 to 3.99 mm2. State University of Rio de Janeiro, Av. 28 de Setembro, 87, Fundos, Vila Isabel, Rio de The thickness of the tunica albuginea varies from 0.029 to 0.296 mm in the dorsal Janeiro, Brazil 20551-030 (e-mail: sampaio.uerj@ region and from 0.014 to 0.113 mm in the ventral region of the corpora cavernosa. gmail.com). Conclusions: We found a strong correlation between the total penile area, corpora cavernosa and corpus spongiosum with fetal age (weeks following conception). The growth rate was more intense during the second trimester (13 to 24 weeks of gestation) compared to the third trimester (25 to 36 weeks). Tunica albuginea thickness also was strongly correlated with fetal age and this struc- ture was thicker in the dorsal vs ventral region.

Key Words: fetus, penis, growth

ACCURATE data on genital develop- morphometric analysis of images ment in humans, especially the penis, such as ultrasound and MRI can are relatively scarce.1e6 Although the be complemented with macroscopic structural components of the penis and mesoscopic data that would present an important role in physi- characterize the growth of penile ology and pathology, there are few structures.8,9 studies on the development in In humans the growth of the penis human fetuses. occurs in 4 stages, ie in early preg- Ultrasonography for assessing the nancy, resulting in an average length external genitalia in utero has been of 3.5 cm in newborns; from birth to 2 used as a tool not only to determine years, when an increase of 1.5 cm is fetal gender, but also to characterize observed; from 2 to 11 years, with an the patterns of normal development.7 additional 1.5 cm growth, and at pu- The different patterns obtained by berty, when the penis reaches adult

0022-5347/13/1905-1876/0 http://dx.doi.org/10.1016/j.juro.2013.05.050 THE JOURNAL OF UROLOGY® Vol. 190, 1876-1883, November 2013 1876 j www.jurology.com © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Printed in U.S.A. PENILE DEVELOPMENT IN HUMAN FETUSES 1877

size.10 The mechanism of growth cessation is still died of causes unrelated to the urogenital tract. The not completely clear.11 fetuses were well preserved and none had any detectable The development of the penis begins at 8 weeks of congenital malformation. Gestational age ranged from 13 gestation. Complete development of the urethra oc- to 36 weeks following conception (corresponding to 15 to curs in the 14th week of pregnancy and the foreskin 38 menstrual weeks) and was estimated by the greatest foot length method.19e22 The fetuses were dissected with a encircles the glans at 21 weeks.6,12,13 The length of magnification glass, and the urogenital bloc containing the penis increases significantly with fetal gesta- kidneys, ureters, bladder, prostate, testes and penis was tional age, from a value of approximately 6.0 mm at removed. We used 1 to 5 fetuses of each gestational age 14,15 16 weeks to 26.4 mm at 38 weeks. Although there (see table). have been studies on penile growth in the fetal period, they are related only to the length of the penis Tissue Sample Preparation based on ultrasound.9,14,16e18 To our knowledge there After dissection the penis was incised close to the pubic are no studies available on the growth of the penile symphysis, around 2 mm from it, cross-sectioned at its area during the fetal period. Our analysis started mid shaft and immediately immersed in 10% formalin during the fetal period, from 13 WPCs, which corre- phosphate buffer solution for 24 hours. Afterward the m sponds to 15 gestational (menstrual) weeks, when samples were embedded in paraffin and sectioned at 5 m with intervals of 200 mm between each section. The sam- the main elements of the penis, such as the corpora ples for histological analysis were obtained from the mid cavernosa, corpus spongiosum and tunica albuginea, shaft of the penis (fig. 1). The sections were stained with are already formed, as evidenced by our data. Masson trichrome for analysis and evaluation of the area We analyzed the growth of the area of the penis of the penis, corpora cavernosa and corpus spongiosum, and erectile structures (corpora cavernosa and and with hematoxylin and eosin for analysis of the tunica corpus spongiosum) and thickness of the tunica albuginea thickness. albuginea during the fetal period (13 to 36 weeks after conception), establishing normative patterns Morphometric Analysis of growth. Precise data on penile area growth dur- All sections were photographed with a digital camera ing the fetal period would be useful for correlation (DP70, Olympus America, Inc., Melville, New York) under with clinical data obtained by ultrasound and the same conditions at a resolution of 2,040 1,536 pixels, directly coupled to the microscope (BX51, Olympus mainly by MRI, which can evaluate the sectional America, Inc.) and stored in a TIFF file. The ImageJ area in vivo. Tracking these data would also be software, version 1.46r, loaded with its own plug-in useful for evaluating and following cases of micro- (http://rsb.info.nih.gov/ij/) was used for penile evaluation penis in utero. (fig. 1). We obtained 5 sections from each penis. We analyzed 1 field on each section and we obtained 3 measurements for MATERIALS AND METHODS each field, considering the deep fascia of the penis (Buck The study protocol was approved by the ethical committee fascia) as the external limit (fig. 1, A). We then obtained on human research at our institution. We studied 56 the mean of these 3 measurements, determining the area penises from fresh normal human fetuses. All fetuses had of the penis.

Area of penis, corpora cavernosa and corpus spongiosum, and thickness of tunica albuginea by WPC

Mean mm2 Area Mean mm2 Area Mean mm Thickness of Mean mm Thickness of Mean mm2 Area of Penis of Corpora of Corpus Tunica Albuginea in the Tunica Albuginea in WPC No. Fetuses (range) Cavernosa (range) Spongiosum (range) Dorsal Region (range) Ventral Region (range) 13 1 0.956 (0.956e0.956) 0.280 (0.280e0.280) 0.140 (0.140e0.140) 0.029 (0.025e0.058) 0.014 (0.013e0.021) 14 5 1.733 (1.414e1.812) 0.393 (0.277e0.531) 0.268 (0.231e0.458) 0.031 (0.024e0.053) 0.021 (0.010e0.025) 15 4 1.470 (1.383e1.557) 0.492 (0.415e0.569) 0.264 (0.202e0.295) 0.041 (0.034e0.048) 0.025 (0.012e0.030) 16 2 3.969 (2.506e5.431) 1.202 (0.913e1.492) 0.624 (0.509e0.738) 0.054 (0.045e0.066) 0.028 (0.020e0.031) 17 4 3.780 (2.934e5.088) 1.642 (1.404e1.936) 0.636 (0.569e0.742) 0.049 (0.045e0.059) 0.038 (0.026e0.044) 18 5 4.607 (4.087e5.127) 1.425 (1.228e1.622) 0.892 (0.808e0.981) 0.043 (0.039e0.061) 0.031 (0.016e0.038) 20 5 10.350 (9.260e10.864) 2.716 (2.534e2.915) 1.019 (0.976e1.784) 0.074 (0.071e0.077) 0.021 (0.021e0.022) 21 4 11.791 (8.304e11.232) 4.903 (3.231e5.371) 1.915 (1.825e2.546) 0.107 (0.106e0.108) 0.073 (0.056e0.083) 22 4 9.727 (9.260e11.731) 3.260 (2.546e4.095) 1.441 (1.245e1.867) 0.171 (0.143e0.219) 0.062 (0.052e0.109) 23 3 10.894 (9.396e12.392) 2.672 (2.654e2.724) 1.435 (1.203e1.668) 0.103 (0.098e0.114) 0.065 (0.049e0.067) 24 4 11.232 (8.290e14.174) 3.050 (1.867e4.233) 1.847 (1.142e2.552) 0.194 (0.164e0.227) 0.084 (0.050e0.109) 25 4 11.731 (10.192e15.158) 4.869 (3.364e5.371) 1.894 (1.207e2.581) 0.156 (0.144e0.168) 0.097 (0.078e0.117) 27 4 17.513 (16.288e18.938) 8.678 (8.348e9.007) 3.469 (3.213e3.725) 0.190 (0.168e0.220) 0.119 (0.092e0.129) 28 1 21.104 (21.104e21.104) 9.866 (9.866e9.866) 3.717 (3.717e3.717) 0.329 (0.300e0.347) 0.134 (0.102e0.144) 29 2 18.956 (13.279e24.633) 5.450 (4.095e6.805) 3.031 (2.482e3.580) 0.174 (0.116e0.206) 0.115 (0.088e0.125) 30 1 19.319 (19.319e19.319) 5.817 (5.817e5.817) 2.578 (2.578e2.578) 0.271 (0.213e0.288) 0.094 (0.084e0.134) 32 1 16.692 (16.692e16.692) 5.013 (5.013e5.013) 3.175 (3.175e3.175) 0.266 (0.236e0.314) 0.096 (0.075e0.108) 33 1 20.770 (20.770e20.770) 8.832 (8.832e8.832) 3.243 (3.243e3.243) 0.293 (0.252e0.319) 0.138 (0.099e0.143) 36 1 24.250 (24.250e24.250) 9.120 (9.120e9.120) 3.990 (3.990e3.990) 0.296 (0.226e0.338) 0.113 (0.098e0.153) 1878 PENILE DEVELOPMENT IN HUMAN FETUSES

Figure 1. Transverse sections of penis demonstrate evaluation of areas of penis and thickness of tunica albuginea (TA) using ImageJ software in fetus at 29 WPCs. A, selection of region of penis to be measured, considering deep penile fascia (Buck fascia, red ring). B, attainment of area of corpora cavernosa (CC, red ring). C, attainment of area of corpus spongiosum (CE, red ring). A to C, Masson trichrome, reduced from 20. D, evaluation of thickness of tunica albuginea in dorsal region (white markers) and ventral region (yellow markers). H&E, reduced from 20.

For evaluation of the area of the corpora cavernosa and analysis by simple linear regression was used to assess the area of the corpus spongiosum we used a similar the association between the variables “thickness” with procedure (fig. 1, B and C). For evaluation of the thickness “gestational age” and “thickness” with “area of the corpora of the tunica albuginea we obtained 5 sections from each cavernosa.” penis. We analyzed 1 field on each section and we obtained 8 measurements for each field (4 in the dorsal re- Statistical Analysis gion and 4 in the ventral region; fig. 1, D). Afterward we With the aid of GraphPad PrismÒ 5.0 software, by using calculated the mean of the 4 measures for each region, the mean values for each fetus we performed statistical determining the thickness of the tunica albuginea sepa- analysis by simple linear regression, assessing the asso- rately for the dorsal and ventral regions. Statistical ciation between the variables analyzed with fetal age and PENILE DEVELOPMENT IN HUMAN FETUSES 1879

other variables. Also the correlation coefficient (r) and to the growth of the area of the penis. Also the p value were obtained for each regression analysis, with growth of the area of the corpus spongiosum and p 0.05 considered to indicate statistical significance. corpora cavernosa is proportional (fig. 5). During the entire fetal period studied the thickness of the tunica albuginea varied from 0.029 to 0.296 mm in RESULTS the dorsal region of the corpora cavernosa and from At 13 weeks after conception the corpora cavernosa, 0.014 to 0.113 mm in the ventral region (fig. 6). corpus spongiosum and tunica albuginea are anatomical structures already defined and well individualized. All analyses for this work were DISCUSSION performed on transverse sections of the mid shaft During the embryonic and fetal periods the trans- region of the penis (fig. 1). The results are presented formations undergone by the different tissue com- in the table and figures 2 to 6, and are presented as ponents are rapid. Organs and tissues undergo the mean of the values found for each gestational significant changes macroscopically and microscop- age analyzed. ically in a short time.13 Therefore, there is a need to During the entire fetal period studied (13 to 36 shorten the interval of observations. For the present WPCs) the value of the area of the penis varied from study we defined the interval to be about 7 days in 0.95 to 24.25 mm2 (see table and fig. 2). The area of the majority of the cases. Analyses were concen- the corpora cavernosa varied from 0.28 to 9.12 mm2 trated on the growth of corpora cavernosa, corpus (fig. 3) and the area of the corpus spongiosum varied spongiosum and tunica albuginea during the fetal from 0.14 to 3.99 mm2 (fig. 4). period in humans. Quantitative analyses and linear regressions We have previously reported on penile growth revealed that the growth of the areas of the corpus during the fetal period.1e4,12,23 The only additional spongiosum and corpora cavernosa is proportional studies available in the literature have been

Figure 2. Correlation between area of penis and fetal age. Points plotted represent values obtained for each week studied. A, correlation during entire fetal period studied. Linear regression indicates area of penis correlates significantly and positively with fetal age (r2 ¼ 0.9330, p 0.0001). B, correlation during second trimester (13 to 24 WPCs). Linear regression indicates area of penis correlates significantly and positively with fetal age (r2 ¼ 0.9037, p 0.0001). C, correlation during third trimester (25 to 36 WPCs). Linear regression indicates area of penis correlates significantly and positively with fetal age (r2 ¼ 0.5653, p 0.0314). 1880 PENILE DEVELOPMENT IN HUMAN FETUSES

Figure 3. Correlation between area of corpora cavernosa and fetal age. Points plotted represent values obtained for each week studied. A, correlation during entire fetal period studied. Linear regression indicates area correlates significantly and positively with fetal age (r2 ¼ 0.7702, p <0.0001). B, correlation during second trimester (13 to 24 WPCs). Linear regression indicates area of corpora cavernosa correlates significantly and positively with fetal age (r2 ¼ 0.7164, p ¼ 0.001). C, correlation during third trimester (25 to 36 WPCs). Linear regression indicates area of corpora cavernosa does not correlate with fetal age during third trimester (r2 ¼ 0.09062, p ¼ 0.4687). performed by ultrasound or other imaging methods in In a more accurate study Perlitz et al evaluated utero, and have dealt only with penile length.8,9,16e18 the length of the penis in 242 fetuses between 14 Johnson and Maxwell studied the length of the and 35 weeks of gestation.14 Penile length was penis in 95 normal fetuses between 16 and 38 weeks measured from the proximal edge of the corpus of gestation (corresponding with 14 to 36 WPCs).16 cavernous to the tip of the glans. The authors found They observed that the length of the penis in- that increases in penile length correlated with creases with fetal gestational age, from an average gestational age, from 7 mm at 14 weeks to 50 mm at of 6 mm at 16 weeks to 26.4 mm at 38 weeks. 35 weeks. They also found that the measurements of Ultrasound studies have sometimes been criticized fetal penile length were strongly correlated with the because some examiners may not consider at the time fetal biometry. of measurement whether the fetal penis is erect, a Danon et al studied 100 fetuses in utero at 22 fact that was noted several decades ago.24 The study to 36 weeks of gestation by ultrasound and found of Johnson and Maxwell was criticized by Jakobovits, values for penile length between 8.6 mm and who identified an image in which the fetal penis was 19.3 mm.18 These authors indicated that a limita- erect.25 Thus, the results of the study are in question, tion of their study was that the fetus could be in full as the authors may have obtained measures in fetal or partial erection or flaccid at the moment of penises in the erect and flaccid states. measurement. Fetal penile erection is a potential In a similar study Zalel et al established a nomo- confounder in ultrasound penile measurements gram of penile length between 14 and 38 weeks especially in the last weeks of pregnancy, when it of gestation after studying 419 fetuses.17 They can occur 1 to 3 times hourly and last from 5 to observed that penile growth strongly correlated with 17 minutes.26 gestational age, and penile length ranged from 3.88 With the use of magnetic resonance imaging, mm at 14 weeks to 23.77 at 38 weeks. Nemec et al studied penile growth in 194 fetuses at PENILE DEVELOPMENT IN HUMAN FETUSES 1881

Figure 4. Correlation between area of corpus spongiosum and fetal age. Points plotted represent values obtained for each week studied. A, correlation during entire fetal period studied. Linear regression indicates area correlates signiﬁcantly and positively with fetal age (r2 ¼ 0.8962, p <0.0001). B, correlation during second trimester (13 to 24 WPCs). Linear regression indicates area of corpora cavernosa correlates signiﬁcantly and positively with fetal age (r2 ¼ 0.8902, p <0.0001). C, correlation during third trimester (25 to 36 WPCs). Linear regression indicates area of corpora cavernosa does not correlate with fetal age (r2 ¼ 0.3483, p ¼ 0.1236).

18 to 34 weeks of gestation.9 Penile length was symphysis pubis). The measure of the outside assessed as outer length (from tip of glans to scrotal length of the penis by MRI was similar to that ob- edge) and total length (from tip of glans to edge of tained by ultrasound in previous works.

Figure 5. A, correlation between area of corpora cavernosa (CC ) and area of corpus spongiosum (CE, CS ) and fetal age during entire fetal period studied. Points plotted represent values obtained for each week studied. Linear regression indicates both areas correlate signiﬁcantly and positively with fetal age (r2 ¼ 0.8854, p <0.0001 and r2 ¼ 0.9453, p ¼ 0.0001). B, correlation between area of corpus spongiosum and area of corpora cavernosa during entire fetal period studied. Points plotted represent values obtained for each week studied. Linear regression indicates areas correlate signiﬁcantly and positively (r2 ¼ 0.9190, p <0.0001). 1882 PENILE DEVELOPMENT IN HUMAN FETUSES

Figure 6. Thickness of tunica albuginea in dorsal (circles, solid line) and ventral regions (triangles, broken line) of corpora cavernosa. A, correlation with fetal age during entire fetal period studied. Linear regression indicates dorsal and ventral thickness correlate signiﬁcantly and positively with fetal age (r2 ¼ 0.8631 and r2 ¼ 0.8186, p <0.0001). B, correlation with area of corpora cavernosa during entire fetal period studied. Linear regression indicates dorsal and ventral thickness correlate signiﬁcantly and positively with area of corpora cavernosa (r2 ¼ 0.7990 and r2 ¼ 0.8726, p <0.0001).

We confirmed that at 13 WPCs the corpora cav- The findings regarding rhythm of penile growth ernosa and corpus spongiosum as well as the tunica according to the trimester are consistent with those albuginea and intracavernous septa are already found previously for kidney growth. Prior studies observed as well individualized anatomical struc- have demonstrated that the kidney has a more tures, and these are the elements that were intense pace of growth in the second trimester.27,28 analyzed in this study (fig. 4). Thus, we evaluate for An additional explanation could be that at 8 to 21 the first time the development of the area of the weeks of gestation male fetuses have peak levels of penis, corpora cavernosa and corpus spongiosum serum testosterone.29 during the entire human fetal period (13 to 36 We also found that the thickness of the tunica WPCs), and during the second (13 to 24 WPCs) and albuginea in fetuses ranged from 0.029 to 0.296 mm third trimesters (25 to 36 WPCs) separately. in the dorsal penile region and from 0.014 to Regarding the total area of the penis, we 0.113 mm in the ventral penile region during the observed a strong positive correlation between fetal period. The thickness increase was directly growth of the total area and gestational age proportional and strongly positively correlated with (average 0.956 mm2 at 13 WPCs to 24.250 mm2 at gestational age and with the area of the penis 36 WPCs; fig. 2). We observed that the area of the (figs. 1 and 6). We also observed and quantified for penis increases with a more intense rhythm in the the first time that the thickness of the tunica albu- early fetal period (second trimester, 13 to 24 WPCs) ginea is consistently and significantly greater in the compared to the third trimester (25 to 36 WPCs). dorsal region, where it is thick, compared to the These findings, with -2 standard deviations, would ventral region, where it thin (figs. 1 and 6). be useful for diagnosis and followup of micropenis Throughout the fetal period the thickness of the in utero. dorsal region is greater, ranging from about 2 to 3 The increase of the area of the corpora cavernosa times thicker, and this difference becomes more also correlated with gestational age and ranged evident at the end of gestation. A previous study of 7 from 0.28 to 9.12 mm2 from 13 to 36 WPCs. We adult cadavers revealed that the tunica albuginea is similarly observed more intense growth in the sec- thicker in the dorsal region and the most vulnerable ond trimester (fig. 3). The area of the corpus spon- area is on its ventral aspect, where most prostheses giosum also correlated with gestational age and tend to extrude. This finding supports the belief that ranged from 0.14 to 3.99 mm2 from 13 to 36 WPCs. prosthesis extrusion often has an anatomical basis More intense growth was similarly observed during and is not merely a phenomenon caused by infection the second trimester (fig. 4). Quantitative analysis or compression.30 and linear correlations showed that the growth of the area of the corpora cavernosa and corpus spongiosum is proportional to the total area of the penis, CONCLUSIONS and the growth of the areas of the corpora cavernosa There is a strong positive correlation between and corpus spongiosum is proportional (fig. 5). the growth of the total penile area, corpus PENILE DEVELOPMENT IN HUMAN FETUSES 1883

cavernous and corpus spongiosum with gestational proportional and shows a strong positive correla- age during the fetal period (13 to 36 WPCs). tion with gestational age. The thickness of the The growth rhythm of the penile area, corpus tunica albuginea is 2 to 3 times greater in the cavernous and corpus spongiosum is more intense dorsal region compared to the ventral region, and in the second trimester of gestation. The growth the difference is more evident at the end of the tunica albuginea thickness is directly of gestation.

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