Talk:Penis Development

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Cite this page: Hill, M.A. (2021, May 15) Embryology Penis Development. Retrieved from


Immunohistochemical expression analysis of the human fetal lower urogenital tract

Shen J, Isaacson D, Cao M, Sinclair A, Cunha GR & Baskin L. (2018). Immunohistochemical expression analysis of the human fetal lower urogenital tract. Differentiation , 103, 100-119. PMID: 30287094 DOI.

Differentiation. 2018 Sep - Oct;103:100-119. doi: 10.1016/j.diff.2018.09.004. Epub 2018 Sep 19.

Shen J1, Isaacson D1, Cao M1, Sinclair A1, Cunha GR1, Baskin L2.

Abstract We have studied the ontogeny of the developing human male and female urogenital tracts from 9 weeks (indifferent stage) to 16 weeks (advanced sex differentiation) of gestation by immunohistochemistry on mid-sagittal sections. Sixteen human fetal pelvises were serial sectioned in the sagittal plane and stained with antibodies to epithelial, muscle, nerve, proliferation and hormone receptor markers. Key findings are: (1) The corpus cavernosum in males and females extends into the glans penis and clitoris, respectively, during the ambisexual stage (9 weeks) and thus appears to be an androgen-independent event. (2) The entire human male (and female) urethra is endodermal in origin based on the presence of FOXA1, KRT 7, uroplakin, and the absence of KRT10 staining. The endoderm of the urethra interfaces with ectodermal epidermis at the site of the urethral meatus. (3) The surface epithelium of the verumontanum is endodermal in origin (FOXA1-positive) with a possible contribution of Pax2-positive epithelial cells implying additional input from the Wolffian duct epithelium. (4) Prostatic ducts arise from the endodermal (FOXA1-positive) urogenital sinus epithelium near the verumontanum. (5) Immunohistochemical staining of mid-sagittal and para-sagittal sections revealed the external anal sphincter, levator ani, bulbospongiosus muscle and the anatomic relationships between these developing skeletal muscles and organs of the male and female reproductive tracts. Future studies of normal human developmental anatomy will lay the foundation for understanding congenital anomalies of the lower urogenital tract. Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. KEYWORDS: Human fetal lower urogenital tract; Immunohistochemical; Sagittal sections PMID: 30287094 DOI: 10.1016/j.diff.2018.09.004

Contrasting mechanisms of penile urethral formation in mouse and human

Differentiation. 2018 May - Jun;101:46-64. doi: 10.1016/j.diff.2018.05.001. Epub 2018 May 17.

Liu G1, Liu X1, Shen J2, Sinclair A2, Baskin L2, Cunha GR3.

Abstract This paper addresses the developmental mechanisms of formation of the mouse and human penile urethra and the possibility that two disparate mechanisms are at play. It has been suggested that the entire penile urethra of the mouse forms via direct canalization of the endodermal urethral plate. While this mechanism surely accounts for development of the proximal portion of the mouse penile urethra, we suggest that the distal portion of the mouse penile urethra forms via a series of epithelial fusion events. Through review of the recent literature in combination with new data, it is unlikely that the entire mouse urethra is formed from the endodermal urethral plate due in part to the fact that from E14 onward the urethral plate is not present in the distal aspect of the genital tubercle. Formation of the distal portion of the mouse urethra receives substantial contribution from the preputial swellings that form the preputial-urethral groove and subsequently the preputial-urethral canal, the later of which is subdivided by a fusion event to form the distal portion of the mouse penile urethra. Examination of human penile development also reveals comparable dual morphogenetic mechanisms. However, in the case of human, direct canalization of the urethral plate occurs in the glans, while fusion events are involved in formation of the urethra within the penile shaft, a pattern exactly opposite to that of the mouse. The highest incidence of hypospadias in humans occurs at the junction of these two different developmental mechanisms. The relevance of the mouse as a model of human hypospadias is discussed. Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. KEYWORDS: External genitalia; Genital tubercle; Hypospadias; Penis; Prepuce; Urethra PMID: 29859371 DOI: 10.1016/j.diff.2018.05.001

Liu X, Liu G, Shen J, Yue A, Isaacson D, Sinclair A, Cao M, Liaw A, Cunha GR & Baskin L. (2018). Human glans and preputial development. Differentiation , 103, 86-99. PMID: 30245194 DOI.

Development of the human penis and clitoris

Differentiation. 2018 Sep - Oct;103:74-85. doi: 10.1016/j.diff.2018.08.001. Epub 2018 Aug 23.

Baskin L1, Shen J2, Sinclair A2, Cao M2, Liu X2, Liu G2, Isaacson D2, Overland M2, Li Y2, Cunha GR2.


The human penis and clitoris develop from the ambisexual genital tubercle. To compare and contrast the development of human penis and clitoris, we used macroscopic photography, optical projection tomography, light sheet microscopy, scanning electron microscopy, histology and immunohistochemistry. The human genital tubercle differentiates into a penis under the influence of androgens forming a tubular urethra that develops by canalization of the urethral plate to form a wide diamond-shaped urethral groove (opening zipper) whose edges (urethral folds) fuse in the midline (closing zipper). In contrast, in females, without the influence of androgens, the vestibular plate (homologue of the urethral plate) undergoes canalization to form a wide vestibular groove whose edges (vestibular folds) remain unfused, ultimately forming the labia minora defining the vaginal vestibule. The neurovascular anatomy is similar in both the developing human penis and clitoris and is the key to successful surgical reconstructions. Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. KEYWORDS: Canalization and fusion; Clitoris; Development; Human; Penis PMID: 30249413 PMCID: PMC6234061 [Available on 2019-09-01] DOI: 10.1016/j.diff.2018.08.001


Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra

Differentiation. 2016 Jul 5. pii: S0301-4681(16)30041-X. doi: 10.1016/j.diff.2016.06.003.

Shen J1, Overland M1, Sinclair A1, Cao M1, Yue X1, Cunha G2, Baskin L1.


We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization ("opening zipper") opens the solid urethral plate into a groove, and fusion ("closing zipper") closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal "cords". Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. KEYWORDS: Clitoris; Development; Epithelial fusion; Penis; SEM; Urethra

PMID 27397682


Histological structure of the medial and lateral walls of cavernous sinus in human fetuses

Childs Nerv Syst. 2015 May;31(5):699-703. doi: 10.1007/s00381-015-2644-3. Epub 2015 Feb 18.

Kural C1, Simsek GG, Guresci S, Arslan E, Kilic C, Tehli O, Geyik M, Erbas C, Izci Y.


PURPOSE: The aim of this study is to elucidate the architecture of these fine structures in human fetuses. METHODS: The histological examination of medial wall (MW) and lateral wall (LW) was performed in 15 normal human fetuses. Eleven fetuses were female and four were male. The gestational age ranged between 14 and 35 weeks. The weight ranged between 180 and 1750 g. The wall samples (two MW and two LW from each fetus) were obtained by microsurgical technique and underwent histological examination. Each wall was examined for the structure and composition of collagen and elastic fibers, ganglions, peripheral nerves, and vessels. RESULTS: A total of 60 wall samples (30 MW and 30 LW) were examined in 15 fetuses. Loose connective tissue composed of type III collagen was observed in both of the walls. Elastic fibers were observed only in three wall samples (two MW and one LW). Ganglion was detected in 11 samples (nine in LW and two in MW), and peripheral nerve was found in 28 walls (18 LW and 10 MW). Vessels were observed in 51 samples (26 LW and 25 MW). None of the walls was stained with type I collagen. CONCLUSIONS: The structure of LW and MW of the cavernous sinus (CS) in fetuses is mainly composed of collagen tissue while some elastic fibers are supported by this tissue. Type III collagen is the main component of fetal CS walls. Because of the weak histological structure, CS may be more prone to tumor invasion in infants. PMID 25690451


Modifications of erectile tissue components in the penis during the fetal period

PLoS One. 2014 Aug 29;9(8):e106409. doi: 10.1371/journal.pone.0106409. eCollection 2014.

Gallo CB1, Costa WS1, Furriel A1, Bastos AL2, Sampaio FJ1.


BACKGROUND: The penile erectile tissue has a complex microscopic anatomy with important functions in the mechanism of penile erection. The knowledge of such structures is necessary for understanding the normal physiology of the adult penis. Therefore, it is important to know the changes of these penile structures during fetal development. This study aims to analyze the development of the main components of the erectile tissue, such as collagen, smooth muscle fibers and elastic system fibers, in human fetuses. METHODOLOGY/PRINCIPAL FINDINGS: We studied the penises of 56 human fetuses aged 13 to 36 weeks post-conception (WPC). We used histochemical and immunohistochemical staining, as well as morphometric techniques to analyze the collagen, smooth muscle fibers and elastic system fibers in the corpus cavernosum and in the corpus spongiosum. These elements were identified and quantified as percentage by using the Image J software (NIH, Bethesda, USA). From 13 to 36 WPC, in the corpus cavernosum, the amount of collagen, smooth muscle fibers and elastic system fibers varied from 19.88% to 36.60%, from 4.39% to 29.76% and from 1.91% to 8.92%, respectively. In the corpus spongiosum, the amount of collagen, smooth muscle fibers and elastic system fibers varied from 34.65% to 45.89%, from 0.60% to 11.90% and from 3.22% to 11.93%, respectively. CONCLUSIONS: We found strong correlation between the elements analyzed with fetal age, both in corpus cavernosum and corpus spongiosum. The growth rate of these elements was more intense during the second trimester (13 to 24 WPC) of gestation, both in corpus cavernosum and in corpus spongiosum. There is greater proportional amount of collagen in the corpus spongiosum than in corpus cavernosum during all fetal period. In the corpus spongiosum, there is about four times more collagen than smooth muscle fibers and elastic system fibers, during all fetal period studied. PMID 25170760


Development of the human foreskin during the fetal period

Histol Histopathol. 2012 Aug;27(8):1041-5. doi: 10.14670/HH-27.1041.

Favorito LA1, Balassiano CM, Costa WS, Sampaio FJ.



Foreskin development begins at twelfth gestational week through a circular invagination of the ectoderm in the glandular periphery that grows ventrally and totally involves the glans around the twentieth gestational week. Studies of foreskin formation chronology and its histological constituents in human fetuses are rare. The objective of this study is to analyze foreskin development during the second trimester of the human fetal period. METHODS: We studied twelve well-preserved human fetuses between thirteen and nineteen weeks post conception (WPC), according to the foot length criterion. The fetuses' weight ranged from 70 to 340 g and the crown-rump length from 11 to 18.5 cm. Their penises were formalin-fixed, paraffin-embedded and cut into 5 micrometers sections. Hematoxylin and eosin, Van Gieson solution, Gomori trichrome and Weigert staining were used. RESULTS: The glans was partially covered by the foreskin in the fetus at 13 WPC and almost completely covered by the foreskin in fetuses at 16 WPC and 17 WPC. The complete foreskin was formed only in the fetuses at 18 and 19 WPC, in which the foreskin totally covered the glans. In all the fetuses studied we observed the presence of preputial lamella and a large amount of mesenchymal tissue between the foreskin and glans. CONCLUSION: The chronology of foreskin formation in the second gestational trimester is well documented in our article. It is a fast process that lasts around five weeks and is coordinated with penile urethra formation. PMID: 22763876 DOI: 10.14670/HH-27.1041