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Objectives: To assess embryonic genital tubercle using transvaginal three-dimensional (3D) ultrasound at 8-10+6 weeks of gestation., Methods: One-hundred and two transvaginal 3D ultrasound scans were performed for first-trimester dating at 8-10+6 weeks of gestation. The genital tubercle angle (GTA) and genital tubercle length (GTL) were measured with a mid-sagittal view of the embryo using the 3D ultrasound multiplanar mode. Intra- and inter-observer agreements regarding GTA and GTL were also assessed with Bland-Altman plots and intra- and inter-correlation coefficients., Results: There were no significant differences in GTA between male and female embryos at 8, 9, 10 weeks, or 8-10+6 weeks of gestation, respectively. There were also no significant differences in GTL between male and female embryos at 8, 9, 10 weeks, or 8-10+6 weeks of gestation, respectively. However, GTL increased linearly with advancing gestation (r=0.8276, p<0.00001). Mean GTL (SD) values at 8, 9, and 10 weeks were 0.833 mm (0.274), 1.623 mm (0.262), and 2.152 mm (0.420), respectively (p<0.001). Intra- and inter-reproducibilities of GTA and GTL were excellent. The intra- and inter-correlation coefficients of GTA and GTL were 0.964 and 0.995, and 0.996 and 0.9933, respectively., Conclusions: The genital tubercle could be identified using transvaginal 3D ultrasound at 8-10+6 weeks of gestation. However, sex differentiation could not be performed at this age. The genital tubercle linearly developed with advancing gestation during the mid-first trimester of pregnancy., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Structural anomalies of the female reproductive tract, known as Mullerian anomalies, can occur in isolation or in association with anomalies of other organ systems. Due to shared embryology, the most common association in up to 40% of patients is with renal, ureteral, and bladder anomalies. Affected girls can have a wide range of genitourinary symptoms with urologists playing an integral role in their diagnosis and treatment. To facilitate the recognition and management of these conditions, we provide a review of Mullerian anomalies including the embryology, classifications, syndromes, evaluation, and treatments with attention to their urologic applicability., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exposures to adverse conditions in utero can lead to permanent changes in the structure and function of key physiological systems in the developing fetus, increasing the risk of disease and premature aging in later postnatal life. When considering the systems that could be affected by an adverse gestational environment, the reproductive system of developing female offspring may be particularly important, as changes have the potential to alter both reproductive capacity of the first generation, as well as health of the second generation through changes in the oocyte. The aim of this review is to examine the impact of different adverse intrauterine conditions on the reproductive system of the female offspring. It focuses on the effects of exposure to maternal undernutrition, overnutrition/obesity, hypoxia, smoking, steroid excess, endocrine-disrupting chemicals, and pollutants during gestation and draws on data from human and animal studies to illuminate underlying mechanisms. The available data indeed indicate that adverse gestational environments alter the reproductive physiology of female offspring with consequences for future reproductive capacity. These alterations are mediated via programmed changes in the hypothalamic-pituitary-gonadal axis and the structure and function of reproductive tissues, particularly the ovaries. Reproductive programming may be observed as a change in the timing of puberty onset and menopause/reproductive decline, altered menstrual/estrous cycles, polycystic ovaries, and elevated risk of reproductive tissue cancers. These reproductive outcomes can affect the fertility and fecundity of the female offspring; however, further work is needed to better define the possible impact of these programmed changes on subsequent generations., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital primordia. Here, we found that the WD mesenchyme under the regulation of Hedgehog (Hh) signaling is closely related to the developmental processes of the FRT during embryonic and postnatal periods. Deficiency of Sonic hedgehog (Shh), the only Hh ligand expressed exclusively in WDs, prevents the MD mesenchyme from affecting uterine growth along the radial axis. The in vivo cell tracking approach revealed that after WD regression, distinct cells responding to WD-derived Hh signal continue to exist in the developing FRT and gradually contribute to the formation of various tissues such as smooth muscle, endometrial stroma and vascular vessel, in the mouse uterus. Our study thus provides a novel developmental mechanism of FRT relying on WD.

Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or "environmentally relevant" doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The spotted hyaena (Crocuta crocuta) is a unique species, even amongst the Hyaenidae. Extreme clitoral development in female spotted hyaenas challenges aspects of the accepted framework of sexual differentiation and reproductive function. They lack a vulva and instead urinate, copulate and give birth through a single, long urogenital canal that traverses a clitoris superficially resembling a penis. Recent and historical evidence is reviewed to describe our changing understanding of the biology of this species. Expanding upon observations from hyaenas in nature, much has been learned from studies utilising the captive colony at the University of California, Berkeley. The steroid environment of pregnancy is shaped by placental androgen and oestrogen secretion and a late gestational increase in sex hormone binding globulin, the regulated expression and steroid-binding characteristics of which are unique within the Hyaenidae. While initial external genital development is largely free of androgenic influence, the increase in testosterone concentrations in late gestation influences foetal development. Specifically, anti-androgen (AA) treatment of pregnant females reduced the developmental influence of androgens on their foetuses, resulting in reduced androstenedione concentrations in young females and easier birth through a 'feminised' clitoris, but precluded intromission and mating by 'feminised' male offspring, and altered social interactions. Insight into the costs and benefits of androgen exposure on spotted hyaena reproductive development, endocrinology and behaviour emphasises the delicate balance that sustains reproductive success, forces a re-evaluation of how we define masculine vs feminine sexual characteristics, and motivates reflection about the representative value of model species.

Genital tubercle has bisexual potential before sex differentiation. Females exposed to androgen during sex differentiation show masculinized external genitalia, but the effects of different androgens on tubular urethral and penile formation in females are mostly unknown. In this study, we compared the masculinization effects of commonly used androgens methyltestosterone, dihydrotestosterone, and testosterone on the induction of penile formation in females. Our results suggested that prenatal treatment with low doses of methyltestosterone, but not same doses of dihydrotestosterone or testosterone, could induce penile formation in female mice. The minimum dose of dihydrotestosterone and testosterone for inducing tubular urethral formation in female mice was, respectively, 50 and 20 times higher than that of methyltestosterone. In vivo methyltestosterone treatment induced more nuclear translocation of androgen receptors in genital tubercles of female mice, affected Wnt signaling gene expressions, and then led to similar patterns of cell proliferation and death in developing genital tubercles to those of control males. We further revealed that low-dose methyltestosterone, but not same dose of dihydrotestosterone or testosterone, treatment induced penile formation in female guinea pigs. Exposure of female mouse genital tubercle organ culture to methyltestosterone, dihydrotestosterone, or testosterone could induce nuclear translocation of androgen receptors, suggesting that the differential effect of the three androgens in vivo might be due to the hormonal profile in mother or fetus, rather than the local genital tissue. To understand the differential role of these androgens in masculinization process involved is fundamental to androgen replacement therapy for diseases related to external genital masculinization., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

Infections of the male and female reproductive system can lead to significant morbidity and mortality. This article will review the relevant embryology and anatomy of the male and female reproductive systems and will discuss the imaging findings of different infections. An understanding of the clinical presentation and imaging findings of infections of the reproductive system is critical in order to allow for prompt and accurate diagnosis. A delay in diagnosis for these infections can have significant morbidity, and occasional mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The prostate is an accessory reproductive gland that is sensitive to the action of exogenous compounds known as endocrine disrupters that alter normal hormonal function. Finasteride is a widely used chemical that acts to inhibit the conversion of testosterone in its most active form, dihydrotestosterone. It is known that intrauterine exposure to finasteride causes changes in the male prostate even at low dosages; however, it is not known whether these dosages are capable of causing changes in the female prostate, which is present in a large number of mammalian species, including humans. In the present study, histochemistry, immunohistochemistry, immunofluorescence, serological dosages, and three-dimensional reconstruction techniques were employed to evaluate the effects of intrauterine exposure to a low dose of finasteride (100 μg.BW/d) on postnatal prostate development in male and female Mongolian gerbils. The results indicate that the gerbil female prostate also undergoes alterations following intrauterine exposure to finasteride, exhibiting a thickening of periductal smooth muscle and increased stromal proliferation. There are also intersex differences in the impact of exposure on the expression of the androgen receptor, which was increased in males, and of the estrogen-α receptor, which was decreased in the male prostate but unchanged in females. Altogether, this study indicates there are sex differences in the effects of finasteride exposure even at low dosages., (© 2019 Wiley Periodicals, Inc.)

In horses, pregnancy is characterized by high levels of maternal estrogens that are produced largely by the interstitial tissue inside the gonads of the offspring, associated with a physiological gonadal hyperplasia, that is uncommon in other species. However, a detailed structural-functional understanding of the early stages of gonadal development and hyperplasia has remained elusive in horse pregnancy because of the lack of substantial data. The goal of this study was to describe the genital organs' development in 19 early horse embryos and fetuses (days 20-140 of gestation) of both sexes by means of anatomy, histology, stereology, and immunohistochemistry, with a specific focus on gonadal hyperplasia and interstitial tissue development. Gonadal hyperplasia with similar amounts of interstitial cells was observed in both sexes, but only during the early stage of development (days 40-90). Surprisingly, a higher degree of hyperplasia, characterized by larger amounts of interstitial cell-rich areas, was seen in fetal ovaries from 90 days of gestation onwards. Another novel aspect was that parallel to the hyperplasia of the interstitial cells, a much more precocious and pronounced differentiation of germinal cells was seen in the ovary, characterized by an earlier peak and decrease of DAZL and OCT protein immune markers. In conclusion, a reduced degree of hyperplasia and interstitial tissue in the fetal testis after 90 days of gestation suggests the existence of a more efficient mechanism regarding the synthesis of estrogen precursors as a structural or physiological difference between both fetal sexes, which warrants further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cysteine‑rich angiogenic inducer 61 (CCN1/Cyr61) is a prompt response transcription product activated by growth factors. As a member of the CCN family, it mediates cell survival, proliferation, differentiation, migration, adhesion and synthesis of the extracellular matrix by binding directly to the integrins and heparin sulfate proteoglycans or activating multiple signaling transduction pathways. It has previously been demonstrated that CCN1/Cyr61 exhibits an important role in the female reproductive system during embryogenesis and tumorigenesis. However, the functions of CCN1/Cyr61 in the female reproductive system have not been systematically investigated, therefore, the primary aim of the present review is to introduce the role and function of CCN1/Cyr61 in the female reproductive system. The current review presents the molecular structure and biological function of CCN1/Cyr61 and provides detailed data on its expression pattern and contribution to the female reproductive system, including the role in embryogenesis and tumorigenesis.

Childbirth can be a traumatic experience on the female body. Some techniques may be implemented to make the process smoother and decrease the potential lacerations that can occur. Episiotomies have been used by obstetricians and midwives to help make the fetal decent down the vaginal canal less turbulent. A physician must use his best judgment on when it is necessary to make this incision and what form of incision to make. Before making an incision one must understand the female external and internal anatomy and thoroughly comprehend the stages of birth to understand how and what complications can occur. Even though an episiotomy is a minor incision, it is still a surgical incision nonetheless and as with any form of surgery there are both risks and benefits that are to be considered. Nevertheless, episiotomies have proven to help ease births that are complicated by shoulder dystocia, prevent severe lacerations, and decrease the second stage of labor. The following comprehensive review provides a description of the female anatomy, as well as an extensive description of why, when, and how an episiotomy is done. Clin. Anat. 30:362-372, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Reciprocal epithelial-mesenchymal interactions and several signalling pathways regulate the development of the genital tubercle (GT), an embryonic primordium of external genitalia. The morphology of the adult male external genitalia of the Asian house musk shrew Suncus murinus (hereafter, laboratory name: suncus) belonging to the order Eulipotyphla (the former order Insectivora or Soricomorpha) differs from those of mice and humans. However, the developmental process of the suncus GT and its regulatory genes are unknown. In the present study, we explored the morphological changes and gene expression patterns during the development of the suncus GT. Morphological observations suggested the presence of common (during the initial outgrowth) and species-specific (during the sexual differentiation of GT) developmental processes of the suncus GT. In gene expression analysis, fibroblast growth factor 8 (Fgf8) and sonic hedgehog (Shh), an indicator and regulator of GT development in mice respectively, were found to be expressed in the cloacal epithelium and the developing urethral epithelium of the suncus GT. This pattern of expression specifically in GT epithelium is similar to that observed in the developing mouse GT. Our results indicate that the mechanism of GT formation regulated by the FGF and SHH signalling pathways is widely conserved in mammals., (© 2017 Society for Reproduction and Fertility.)

The molecular signaling processes involved the differentiation of the Müllerian duct (MD) into the female reproductive tract, or oviduct, in non-mammalian vertebrates are not well understood. Studies in mammals and birds indicate that steroid hormones play a role in this process, as the embryonic MD has been shown to be vulnerable to exogenous estrogens and progestins and environmental endocrine disrupting contaminants. In a previous study, developmental treatment with an estrogen receptor α (ERα) agonist, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), induced significant enlargement of the MD in alligator embryos incubated at a male-producing temperature, which was not observed in embryos treated with an estrogen receptor β (ERβ) agonist, 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), or with 17β-estradiol (E 2 ). In order to understand the role of estrogen signaling in female alligator oviduct development, we incubated eggs at a female-producing temperature and treated them with E 2 and these ER selective agonists, PPT and WAY 200070, just prior to the thermosensitive window of sex determination. At stage 27, one stage prior to hatching, PPT induced significant enlargement of the MD with precocious development of secretory glands and connective tissue differentiation similar to characteristics of mature adult oviduct. PPT treatment in ovo increased mRNA expression of ERβ, progesterone receptor, androgen receptor and insulin-like growth factor 1 in MD at stage 27, while expression of ERα was decreased. Neither WAY 200070 nor E 2 treatment induced these effects seen in PPT-treated MD. The results of this study provide insight into the critical factors for healthy reproductive system formation in this sentinel species, although further investigation is needed to determine whether the observed phenomena are directly due to selective stimulation of ERα or related to some other aspect of PPT treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Early ultrasound fetal sex determination is of obvious interest, particularly in the context of X-linked diseases. In the human, the anogenital distance, i.e., the distance between the caudal end and the base of the genital tubercule is sexually dimorphic. This difference is apparent from 11 weeks of gestation. The aim of this prospective study was to evaluate the accuracy of anogenital distance measurement during the first trimester ultrasound in the early determination of fetal gender., Materials and Methods: Fetal gender was assessed by ultrasound in 310 singleton pregnancies at 11-14 weeks of gestation. The optimal cut-off was determined by the minimal p-value technic and validated using bootstrap simulation., Results: 310 women were included. A cut-off of 4.8mm was determined to predict male (≥4.8mm) or female (<4.8mm) fetuses. Sex was correctly determined for 87% of the males and 89% of the females. The inter-observer variability was excellent., Conclusion: This study presents a new sonographic sign for early fetal sex determination that has not been previously explored. It appears to be an accurate tool but it requires further validation in larger series., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Common uterine anomalies are important owing to their impact on fertility, and complex mesonephric anomalies and certain Müllerian malformations are particularly important because they cause serious clinical symptoms and affect woman's quality of life, in addition to creating fertility problems. In these cases of complex female genital tract malformations, a correct diagnosis is essential to avoid inappropriate and/or unnecessary surgery. Therefore, acquiring and applying the appropriate embryological knowledge, management and therapy is a challenge for gynaecologists. Here, we considered complex malformations to be obstructive anomalies and/or those associated with cloacal and urogenital sinus anomalies, urinary and/or extragenital anomalies, or other clinical implications or symptoms creating a difficult differential diagnosis., Methods: A diligent and comprehensive search of PubMed and Scopus was performed for all studies published from 1 January 2011 to 15 April 2015 (then updated up to September 2015) using the following search terms: 'management' in combination with either 'female genital malformations' or 'female genital tract anomalies' or 'Müllerian anomalies'. The MeSH terms 'renal agenesis', 'hydrocolpos', 'obstructed hemivagina' 'cervicovaginal agenesis or atresia', 'vaginal agenesis or atresia', 'Herlyn-Werner-Wunderlich syndrome', 'uterine duplication' and 'cloacal anomalies' were also used to compile a list of all publications containing these terms since 2011. The basic embryological considerations for understanding female genitourinary malformations were also revealed. Based on our experience and the updated literature review, we studied the definition and classification of the complex malformations, and we analysed the clinical presentation and different therapeutic strategies for each anomaly, including the embryological and clinical classification of female genitourinary malformations., Results: From 755 search retrieved references, 230 articles were analysed and 120 studied in detail. They were added to those included in a previous systematic review. Here, we report the clinical presentation and management of: agenesis or hypoplasia of one urogenital ridge; unilateral renal agenesis and ipsilateral blind or obstructed hemivagina or unilateral cervicovaginal agenesis; cavitated and non-communicating uterine horns and Müllerian atresias or agenesis, including Rokitansky syndrome; anomalies of the cloaca and urogenital sinus, including congenital vagino-vesical fistulas and cloacal anomalies; malformative combinations and other complex malformations. The clinical symptoms and therapeutic strategies for each complex genitourinary malformation are discussed. In general, surgical techniques to correct genital malformations depend on the type of anomaly, its complexity, the patient's symptoms and the correct embryological interpretation of the anomaly. Most anomalies can typically be resolved vaginally or by hysteroscopy, but laparoscopy or laparotomy is often required as well. We also include additional discussion of the catalogue and classification systems for female genital malformations, the systematic association between renal agenesis and ipsilateral genital malformation, and accessory and cavitated uterine masses., Conclusions: Knowledge of the correct genitourinary embryology is essential for the understanding, study, diagnosis and subsequent treatment of genital malformations, especially complex ones and those that lead to gynaecological and reproductive problems, particularly in young patients. Some anomalies may require complex surgery involving multiple specialties, and patients should therefore be referred to centres that have experience in treating complex genital malformations., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Correct sexual development is arguably the most important trait in an organism's life history since it is directly related to its genetic fitness. The developing gonad houses the germ cells, the only legacy we pass on to subsequent generations. Given the pivotal importance of correct reproductive function, it is confounding that disorders of sex development (DSDs) are among the most common congenital abnormalities in humans (Lee et al. J Pediatr Urol 8(6):611-615, 2012). Urogenital development is a highly complex process involving coordinated interactions between molecular and hormonal pathways in a tightly regulated order. The controls that regulate some of the key events in this process are beginning to be unraveled. This chapter provides an overview of our understanding of urogenital development from the gonads to the urogenital ducts and external genitalia.

Epithelial ovarian cancer comprises ∼85% of all ovarian cancer cases. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is lacking. Various hypotheses have been proposed over the past several decades to explain the etiology of the disease. The role of reproductive hormones in epithelial ovarian carcinogenesis remains a key topic of research. Primary questions in the field of ovarian cancer biology center on its developmental cell of origin, the positive and negative effects of each class of hormones on ovarian cancer initiation and progression, and the role of the immune system in the ovarian cancer microenvironment. The development of the female reproductive tract is dictated by the hormonal milieu during embryogenesis. Intensive research efforts have revealed that ovarian cancer is a heterogenous disease that may develop from multiple extra-ovarian tissues, including both Müllerian (fallopian tubes, endometrium) and non-Müllerian structures (gastrointestinal tissue), contributing to its heterogeneity and distinct histologic subtypes. The mechanism underlying ovarian localization, however, remains unclear. Here, we discuss the role of reproductive hormones in influencing the immune system and tipping the balance against or in favor of developing ovarian cancer. We comment on animal models that are critical for experimentally validating existing hypotheses in key areas of endocrine research and useful for preclinical drug development. Finally, we address emerging therapeutic trends directed against ovarian cancer., (© 2015 Society for Endocrinology.)

HOX genes convey positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Müllerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 expression has been identified as a mechanism of the decreased implantation associated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx. Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility., (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: The developmental processes of the genital tubercle (GT), the anlage of the external genitalia, possess several developmental aspects, including GT outgrowth, urethral tube formation, and epithelial differentiation of the urethra. The GT comprises the mesenchyme derived from the lateral mesoderm, ectodermal epithelium, and endodermal epithelium (embryonic urethral epithelium). The three tissue layers develop the GT coordinately., Results: Around the initial stage of GT outgrowth (E11.5), FGF signaling was detected in the mesenchyme of the GT. FGF signaling was detected in the three tissue layers of the GT around the early stage of urethral formation (E13.5). Subsequently, FGF signaling was predominantly detected in the urethral epithelium (E14.5). Tissue-specific roles of FGF signaling in GT development were revealed by conditional Fgfr gene knockout approaches. Mesenchymal FGF signaling in the early-stage GT is required for its outgrowth. Ectodermal FGF signaling in the GT is required for the differentiation of the ectoderm and urethral epithelium at their junction to form the proper urethral tube. Endodermal FGF signaling in the GT is required for the stratification and cell adhesive characteristics of the urethral epithelium., Conclusions: The current study suggests that spatiotemporally regulated FGF signaling plays tissue-specific roles in multiple processes of external genitalia development., (© 2015 Wiley Periodicals, Inc.)

Background: Approximately 7% of girls will have an anatomic abnormality in their reproductive tract, diagnosed before or after puberty., Objective: It is important for providers to be aware of the obstructive reproductive tract conditions, the way in which various conditions present, and the way in which such conditions should be managed., Design: Systematic review of the literature using the GRADE evidence system., Results: There is limited data in most areas of obstructive reproductive tract anomalies; however, some retrospective and prospective series with small numbers are still useful to guide clinical practice., Conclusions: Recommendations are based on limited or inconsistent scientific evidence. Recommendations are based primarily on consensus and expert opinion., (Copyright © 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

FOXL2 loss of function in goats leads to the early transdifferentiation of ovaries into testes, then to the full sex reversal of XX homozygous mutants. By contrast, Foxl2 loss of function in mice induces an arrest of follicle formation after birth, followed by complete female sterility. In order to understand the molecular role of FOXL2 during ovarian differentiation in the goat species, putative FOXL2 target genes were determined at the earliest stage of gonadal sex-specific differentiation by comparing the mRNA profiles of XX gonads expressing the FOXL2 protein or not. Of these 163 deregulated genes, around two-thirds corresponded to testicular genes that were up-regulated when FOXL2 was absent, and only 19 represented female-associated genes, down-regulated in the absence of FOXL2. FOXL2 should therefore be viewed as an antitestis gene rather than as a female-promoting gene. In particular, the key testis-determining gene DMRT1 was found to be up-regulated ahead of SOX9, thus suggesting in goats that SOX9 primary up-regulation may require DMRT1. Overall, our results equated to FOXL2 being an antitestis gene, allowing us to propose an alternative model for the sex-determination process in goats that differs slightly from that demonstrated in mice., (© 2014 by the Society for the Study of Reproduction, Inc.)

Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.

Introduction: Since 1836 and the first description of the recto-genital fascia by Charles Denonvilliers, many anatomists have shown interest in this subject. Recently, pelvic surgeons have in turn shown similar interest, for they consider that perfect knowledge of this anatomical domain is crucial for optimal nerve conservation during surgery. Thanks to new anatomical description techniques, fascia location and relationships with pelvic nerves now appear clearer., Objectives: To describe and represent Denonvilliers' fascia and its relationships in the female foetus at different stages of gestation and in three-dimensional space (3D)., Materiel/patients and Methods: Computer-assisted anatomical dissection technique was used. Serial histological sections were made from four human female foetuses. Sections were treated with conventional staining, as well as with nerve and smooth muscle immunostaining. Finally, the sections were digitalized and reconstructed in 3D., Results: Denonvilliers' fascia was clearly located and visualized in three dimensions. It was present in the female foetus, being distinct from the fascia propria of the rectum. It appeared to be composed of multiple parallel layers situated between the vagina and the rectum. From a lateral view, it had an asymmetrical "Y-shaped" aspect that seemed to play the role of a protective sheet for the neurovascular bundles., Conclusion: This study betters our comprehension of the Denonvilliers' fascia in the female foetus and of its connections with pelvic nerves. It also provides a better understanding of safe planes during pelvic dissection. These findings also suggest a biomechanical theory for embryological origin of the Denonvilliers' fascia.

Methoxychlor is an organochlorine pesticide having a weak estrogenicity, which is estimated to be approximately 1000- to 14,000-fold less potent to a natural ligand, 17β-estradiol. However, its active metabolite, hydroxyphenyltrichloroethane, has much more potent estrogenic activity and probably acts in the target organs of animals exposed to methoxychlor at least 100 times stronger than the parent compound. A variety of in vivo reproductive toxicity studies have shown that treatment with methoxychlor exerts typical endocrine-disrupting effects manifest as estrogenic effects, such as formation of cystic ovaries resulting in ovulation failures, uterine hypertrophy, hormonal imbalances, atrophy of male sexual organs, and deteriorations of sperm production in rats and/or mice, through which it causes serious reproductive damages in both sexes of animals at sufficient dose levels. However, methoxychlor is not teratogenic. The no-observed-adverse-effect level of methoxychlor among reliable experimental animal studies in terms of the reproductive toxicity is 10 ppm (equivalent to 0.600 mg/kg/day) in a two-generation reproduction toxicity study., (© 2014 Elsevier Inc. All rights reserved.)

The Müllerian duct (MD) forms the female reproductive tract (FRT) consisting of the oviducts, uterus, cervix, and upper vagina. FRT function is vital to fertility, providing the site of fertilization, embryo implantation and fetal development. Developmental defects in the formation and diseases of the FRT, including cancer and endometriosis, are prevalent in humans and can result in infertility and death. Furthermore, because the MDs are initially formed regardless of genotypic sex, mesenchymal to epithelial signaling is required in males to mediate MD regression and prevents the development of MD-derived organs. In males, defects in MD regression result in the retention of FRT organs and have been described in several human syndromes. Although to date not reported in humans, ectopic activation of MD regression signaling components in females can result in aplasia of the FRT. Clearly, MD development is important to human health; however, the molecular mechanisms remain largely undetermined. Molecular genetics studies of human diseases and mouse models have provided new insights into molecular signaling during MD development, regression and differentiation. This review will provide an overview of MD development and important genes and signaling mechanisms involved.

Background: Planar cell polarity (PCP) signaling regulates the coordinated polarization of cells and is required for the normal development and function of many tissues. Previous studies have identified conserved PCP genes, such as Van Gogh-like 2 (Vangl2) and Prickle (Pk), in the regulation of coordinated orientation of inner ear hair cells and female reproductive tract development. Testin shares a PET-LIM homology with Pk. It is not clear whether Testin acts in PCP processes in mammals., Results: We identified Testin as a Vangl2-interacting protein through a 2-hybrid screen with a cochlea cDNA library. Testin is enriched to cell-cell boundaries in the presence of Vangl2 in cultured cells. Genetic inactivation of Testin leads to abnormal hair cell orientation in the vestibule and cellular patterning defects in the cochlea. In addition, Testin genetically interacts with Vangl2 to regulate hair cell orientation in the cochlea and the opening of the vaginal tract., Conclusions: Our findings suggested Testin as a gene involved in coordinated hair cell orientation in the inner ear and in female reproductive tract development. Furthermore, its genetic interaction with Vangl2 implicated it as a potential molecular link, responsible for mediating the role of Vangl2-containing membranous PCP complexes in directing morphologic polarization., (Copyright © 2013 Wiley Periodicals, Inc.)

Congenital breast and genital tract anomalies are seen frequently in the care of children and adolescents. Breast and internal gynecologic anomalies more often present in adolescence than in early childhood. Management is best delivered through a multidisciplinary team approach. Carefully timed surgical intervention is of importance to optimize psychological, aesthetic and functional outcomes. An understanding of the female breast and genital tract embryology and anatomy is important for a meticulous clinical examination and appropriate surgical treatment. This article will review the normal embryology and anatomy of the adolescent female breast and genital tract., (Copyright © 2012 Wiley-Liss, Inc.)

Separating digestive and urinary outlets is a critical step during mammalian embryogenesis. However, the natural history of these structures is poorly studied, and little is known about their embryonic origin. Here, we show that peri-cloacal mesenchymal (PCM) progenitors are the major source of these structures. Surprisingly, PCM progenitors also contribute to perineum, a structural barrier separating the urinary and digestive tracts, suggesting a potential role of PCM progenitors in establishing independent urinary and digestive outlets. We demonstrate that Six1 and Six2 are complementarily but asymmetrically expressed in the PCM progenitors. Deletion of these genes results in decreased cell survival and proliferation, and consequently in agenesis of the perineum and severe hypoplasia of the genital tubercle. Together, these findings suggest that PCM progenitors are the unexpected source of perineum and genital tubercle, and establish a basic framework for investigating normal and abnormal development of anorectal and genitourinary structures.

Masculinization is programmed by androgen exposure during a masculinization programming window (MPW). Deficiency in MPW androgen action results in reduced size of all reproductive organs and anogenital distance (AGD) and reproductive disorders. Although timing of MPW closing has been defined, what determines 'opening' and 'closing' of the MPW remains unknown. To test whether initiation of testosterone production/action defines the opening of the window, we first demonstrated that androgen receptor mRNA and protein are expressed prior to the MPW, and then investigated whether masculinization could be advanced or enhanced by treating pregnant rats with either 1 or 10 mg/kg/day dihydrotestosterone (DHT) prior to (early window, EW; e11.5-e14.5) or during the MPW (e15.5-e18.5), and then evaluating offspring in foetal life (e18.5, e21.5), early puberty (day 25) or adulthood (∼day 75). DHT treatment did not affect pregnancy duration, birth, litter or pup size. DHT exposure in either time window did not advance foetal male development (Wolffian duct coiling) and had no effect on AGD, testis, penis and ventral prostate (VP) size at any age when measured; there was a tendency towards smaller penis size. In contrast, exposure of females to 10 mg DHT in either time window induced varying degrees of masculinization, including stabilization of the Wolffian duct and increased AGD (e21.5, Pnd25), VP formation, more male-like phallus structure, absence of nipples and vaginal opening and, in some adult females, gross fluid distension of the uterus (hydrometrocolpos); these effects were generally more pronounced after exposure in the MPW than in the EW. In conclusion, exposure of the male rat foetus to additional androgens prior to or during the MPW does not advance or enhance any measured parameter of reproductive development. Therefore, androgen availability plays no role in determining timing of the MPW. Susceptibility of the female reproductive system to androgens may precede the MPW., (© 2012 The Authors. International Journal of Andrology © 2012 European Academy of Andrology.)

The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed., (Copyright © 2011 Wiley Periodicals, Inc.)

The female gubernaculum is an embryonic structure that gives rise to the uterine round ligament and seems to be important in Müllerian development. In the absence of androgens and anti-Müllerian hormone, the paramesonephric or Müllerian ducts complete their invagination and development, interfering with the connection of the tissue column that begins at the inguinal cone (the gubernaculum) and targets the mesonephric duct and caudal ligament of the gonad. The gubernaculum then grows over the Müllerian ducts, incorporating its muscular fibres. Outside and above this point, the Müllerian ducts give rise to the Fallopian tubes, whereas medially to the point of insertion of the gubernaculum, the Müllerian ducts develop into the normal uterus, the adequate formation of which is also induced by the mesonephric ducts. Diverse human anatomical and physiological characteristics such as the simplex uterus, as well as pathological conditions and certain female genital malformations, could be related to gubernaculum dysfunction. The main conclusions in this article are: (1) The female gubernaculum is the origin of the uterine round ligament but probably not of the uteroovarian ligament. Gubernacula are composed of muscular fibres that probably derive from the abdominal wall and that, when fixed and fused with the Müllerian ducts, allow or induce, together with the mesonephric ducts, the adequate development and formation of the uterus. (2) The female gubernaculum seems to be responsible for many of the specific human characteristics of Müllerian development, including the uterus simplex, the anteflexion and low intra-abdominal position of the uterus, and the disposition of uterine muscular fibres. (3) The female gubernaculum seems to be related to pathologies arising from the round ligaments and inguinal hernia. Likewise, certain uterine malformations (e.g., didelphys uterus, Rokitansky syndrome) and accessory and cavitated uterine masses might be related to gubernaculum dysfunction., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Abnormal renal development results in congenital anomalies of the kidney and urinary tract. As many studies suggest that renal malformations are more often found on the left side, a meta-analysis was performed on the distribution of five different unilateral anomalies: multicystic dysplastic kidney, renal agenesis/aplasia, renal ectopia, pelviureteral junction obstruction, and non-obstructive non-refluxing megaureter. Of these anomalies, the left side was affected in 53%, 57%, 56.9%, 63.2%, and 62.5% of patients, respectively, significantly different when compared with an anticipated 50% of left-sided anomalies. An exception to this left-side predominance was found in females with combined genital anomalies and unilateral renal agenesis that commonly present on the right side. The exact mechanisms leading to these lateralizations remain to be determined but may involve vascular development, differential gene expression, or susceptibility to environmental factors such as hypoxia. This remains largely speculative, however, illustrating our limited knowledge of embryogenesis in general and nephrogenesis in particular.

During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.

During male sexual differentiation, the transforming growth factor-β (TGF-β) signaling molecule anti-Müllerian hormone (AMH; also known as Müllerian inhibiting substance, MIS) is secreted by the fetal testes and induces regression of the Müllerian ducts, the primordia of the female reproductive tract organs. Currently, the molecular identity of downstream events regulated by the AMH signaling pathway remains unclear. We found that male-specific Wnt4 expression in mouse Müllerian duct mesenchyme depends upon AMH signaling, implicating the WNT pathway as a downstream mediator of Müllerian duct regression. Inactivation of β-catenin, a mediator of the canonical WNT pathway, did not affect AMH signaling activation in the Müllerian duct mesenchyme, but did block Müllerian duct regression. These data suggest that β-catenin mediates AMH signaling for Müllerian duct regression during male sexual differentiation.

Objectives: To evaluate the accuracy of three-dimensional (3D) ultrasound in fetal gender assignment in the first trimester., Methods: A series of pregnant women attending at 11 to 13 + 6 weeks for the nuchal translucency (NT) scan were enrolled into the study. An ultrasound volume of each fetus was obtained and stored for offline analysis. On the reconstructed mid-sagittal plane, the angle between the genital tubercle and an imaginary line passing tangentially through the fetal back (genital angle) was estimated and a receiver-operating characteristics (ROC) curve was constructed to determine the best cut-off for genital angle in fetal male gender determination. Fetal gender was subsequently ascertained in all cases. To calculate the interobserver variability, a second operator repeated the measurements., Results: There were 85 cases included in the study. The genital angle in males was significantly higher than that in females (51.2 ± 11.3° (n = 36) vs. 18.9 ± 4.1 (n = 49), P < 0.001). The ROC curve revealed the estimated genital angle to have a high degree of accuracy in fetal gender determination (area under the curve ± SE = 1.000 ± 0.001). The best cut-off for male gender determination was found to be between 27° and 29° (sensitivity, 100%; specificity, 98.0%). There was a high degree of correlation between the two operators (r(2) = 0.998; coefficient of variation = 5.4%)., Conclusions: 3D ultrasound is a highly accurate and reproducible tool for fetal gender assignment prior to 14 weeks of gestation., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Sexual health is vital to overall well-being. Orgasm is a normal psycho-physiological function of human beings and every woman has the right to feel sexual pleasure. The anatomy of the vulva and of the female erectile organs (trigger of orgasm) is described in human anatomy textbooks. Female sexual physiology was first described in Dickinson's textbook in 1949 and subsequently by Masters and Johnson in 1966. During women's sexual response, changes occur in the congestive structures that are essential to the understanding of women's sexual response and specifically of their orgasm. Female and male external genital organs arise from the same embryologic structures, i.e. phallus, urogenital folds, urogenital sinus and labioscrotal swellings. The vulva is formed by the labia majora and vestibule, with its erectile apparatus: clitoris (glans, body, crura), labia minora, vestibular bulbs and corpus spongiosum. Grafenberg, in 1950, discovered no "G-spot" and did not report an orgasm of the intraurethral glands. The hypothetical area named "G-spot" should not be defined with Grafenberg's name. The female orgasm should be a normal phase of the sexual response cycle, which is possible to achieve by all healthy women with effective sexual stimulation. Knowledge of the embryology, anatomy and physiology of the female erectile organs are important in the field of women's sexual health., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The morphology and physiology of both the vulva and vagina undergo characteristic age-related changes over a lifetime. At birth, these tissues exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina mature under the influence of adrenal and gonadal steroid hormones. During the reproductive years, the vagina responds to ovarian steroid hormone cycling, and both tissues adapt to the needs of pregnancy and delivery. Following menopause, the vulva and vagina atrophy. A rise in the prevalence of incontinence among older women increases the risk of vulvar and perineal dermatitis. This chapter covers the morphology and physiology of the genital area from infancy to old age., (Copyright © 2011 S. Karger AG, Basel.)

Insulin-like 3 (INSL3) signaling directs fetal gubernacular development and testis descent, but the actions of INSL3 in the gubernaculum are poorly understood. Using microarray gene expression profiling of fetal male rat gubernaculum explants exposed to 10 or 100 nM INSL3, significant changes in expression were identified for approximately 900 genes. Several of the genes showing the largest inductions regulate neuronal development or activity, including Pnoc (34-fold), Nptx2 (9-fold), Nfasc (4-fold), Gfra3 (3-fold), Unc5d (3-fold), and Crlf1 (3-fold). Bioinformatics analysis revealed BMP and WNT signaling pathways and several gene ontologies related to neurogenesis were altered by INSL3. Promoter response elements significantly enriched in the INSL3-regulated gene list included consensus sequences for MYB, REL, ATF2, and TEF transcription factors. Comparing in vivo gene expression profiles of male and female rat fetal gubernaculum showed expression of the Bmp, Wnt, and neurodevelopmental genes induced by INSL3 was higher in males. Using quantitative RT-PCR, the microarray data were confirmed, and the induction of Bmp3, Chrdl2, Crlf1, Nptx2, Pnoc, Wnt4, and Wnt5a mRNA levels were examined over a range of INSL3 concentrations (0.1-100 nM) in male and female gubernaculum. In both sexes, an increasing gene expression response was observed between 0.1 and 10 nM INSL3. These data suggest that INSL3 signaling in the fetal gubernaculum induces morphogenetic programs, including BMP and WNT signaling, and support other rodent data suggesting a role for these pathways in development of the gubernaculum.

Purpose of Review: Müllerian anomalies include a fascinating constellation of congenital malformations. There is significant diversity in anatomic variants and their respective long-term sexual and reproductive outcomes. We review the current controversies in classification and management of vaginal, uterine, and fallopian tube anomalies., Recent Findings: Comparative trials of preoperative magnetic resonance imaging (MRI) and laparoscopic intraoperative evaluation have demonstrated a moderately well correlated prediction of anatomic description. Three-dimensional ultrasound technology appears to be equivalent to MRI in detecting uterine anomalies; however MRI is a consistently superior method of evaluating the vaginal and cervical anatomy. Despite advances in both modalities, care at an experienced center is most highly associated with an accurate preoperative diagnosis and a decrease in the number of inappropriate surgical procedures.Large case series continue to be the main vehicle by which treatment and surgical management of these unique anomalies are described and recommended. Case reports continue to provide information on novel approaches to improve operative techniques. In the absence of prospective studies, these series provide the only emerging information on the long-term sexual and reproductive function of women with vaginal and uterine anomalies., Summary: Recent developments in three-dimensional ultrasonography and MRI improve our ability to accurately describe and diagnose female reproductive tract anomalies. With the description of new complex malformations, which do not fall into the recognized American Society of Reproductive Medicine, formerly American Fertility Society (AFS) classification system, questions arise regarding embryologic development upon which this classification system is based and support attempts to devise a new, comprehensive classification. Advances in surgical correction have expanded the options for the reconstructive surgeon when approaching a patient with an anomaly of the reproductive tract.

Endometriosis is a chronic gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Exposure to endocrine disruptors during critical period of development causes long-lasting effects, being the genital system one of the targets. This study describes the effects on female genital system caused by developmental exposure to the endocrine-disrupting chemical bisphenol A (BPA) during pre- and peri-natal development in mice. To this end, timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with BPA (100, or 1000 microg/kg/day). After delivery, pups were held for 3 months; then, pelvic organs were analyzed in their entirety and livers of both pups and moms were studied for the presence of BPA. We found in the adipose tissue surrounding the genital tracts of a consistent number of treated animals, endometriosis-like structure with the presence of both glands and stroma and expressing both estrogen receptor and HOXA-10. Moreover, cystic ovaries, adenomatous hyperplasia with cystic endometrial hyperplasia and atypical hyperplasia were significantly more frequent in treated animals respect to the controls. Finally, BPA was found in the livers of exposed moms and female offspring. In conclusion, we describe for the first time an endometriosis-like phenotype in mice, elicited by pre-natal exposition to BPA. This observation may induce to thoroughly reconsider the pathogenesis and treatment of endometriosis, considering the high incidence of endometriosis and the problems caused by associated infertility., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Prenatal androgens are generally assumed to permanently affect the morphology of external genitalia. In laboratory rodents, the ano-genital distance index (AGDI) has become widely used as a marker of natural prenatal masculinization. A greater value should indicate a greater masculinization. The aim of this study was to assess the developmental stability of the AGDI in female mice during pre- (Days 1-21) and postweaning (Days 21-61) periods. Presuming that the AGDI reflects a permanent effect of prenatal masculinization, we hypothesized that the AGDI will be a developmentally stable morphometric measurement (interindividual differences in the AGDI measurement should persist over time). In contrast to our prediction, the AGDI showed poor repeatability both during pre- (.15) and postweaning (.22) periods, indicating developmental instability. (A value of 1 indicates perfect repeatability and a value of 0 indicates no repeatability.) The AGDI thus does not seem to be a reliable marker of prenatal female masculinization.

Unlabelled: Recent studies claim that researchers are challenged to find out the pathogenesis of the congenital anomalies of the female reproductive tract. Their frequency is estimated to be between 0.1% and 3% of live births in humans. During the experiments a number of genes were detected to contribute to the formation and development of the female reproductive tract. This review article aims to report these genes, as they probably play a significant role in the pathology of the reproductive tract in females., Target Audience: Obstetricians & Gynecologists, Family Physicians., Learning Objectives: After completion of this educational activity, the participant should be better able to explain the genetic basis of Mullerian abnormalities, give examples of the complexity of the genetic basis behind a variety of mechanisms of disease, and recall the embryology of the female reproductive tract.

A specimen of accessory phallic urethra duplication (triplication) in a 32.5-week gestation female was studied histologically. The specimen demonstrated an anterior "phallic urethra" ending inside a penoclitoral organ in a megalourethra-like dilatation with a narrow epispadiac meatus and "anterior urethrocutaneous fistula" and a posterior canal opening with the anal canal. With histology suggestive of a split persistent urogenital sinus, correlation to normal development strongly suggests an error in the formation of the cloacal membrane and developing superficial cloaca at 26 to 29 days' ovulation age (2 to 4 mm), causing an isolated interruption of the membrane by mesenchyme, which by participating in the growth of the early cloaca may extend as far as the vaginal orifice later. Differences in number, position, and size of such mesenchymal interruptions can explain other duplications and triplications and offer a single alternative for the many current theories of pathogenesis, none of which are compatible with new insights in normal development.

Dicer encodes a riboendonuclease required for microRNA biosynthesis. Dicer was inactivated in Müllerian duct mesenchyme-derived tissues of the reproductive tract of the mouse, using an Amhr2-Cre allele. Although Amhr2-Cre; Dicer conditional mutant males appeared normal and were fertile, mutant females were infertile. In adult mutant females, there was a reduction in the size of the oviducts and uterine horns. The oviducts were less coiled compared to controls and cysts formed at the isthmus near the uterotubal junction. Unfertilized, degenerate oocytes were commonly found within these cysts, indicating a defect in embryo transit. Beads transferred into the mutant oviduct failed to migrate into the uterus. In addition, blastocysts transferred directly into the mutant uterus did not result in pregnancy. Histological analysis demonstrated that the mutant uterus contained less glandular tissue and often the few glands that remained were found within the myometrium, an abnormal condition known as adenomyosis. In adult mutants, there was ectopic expression of Wnt4 and Wnt5a in the luminal epithelium (LE) and glandular epithelium (GE) of the uterus, and Wnt11 was ectopically expressed in GE. These results demonstrate that Dicer is necessary for postnatal differentiation of Müllerian duct mesenchyme-derived tissues of the female reproductive tract, suggesting that microRNAs are important regulators of female reproductive tract development and fertility.

The aim of this work was to determine the ideal moment to sex goat and sheep fetuses, to compare the average time of genital tubercle (GT) migration between sexes, breeds and species, and to evaluate the accuracy of fetal sexing between sexes. A total of 317 fetuses of 219 pregnant females were monitored at 24-hour interval, from days 30 to 60 of pregnancy in ewes, and from days 40 to 60 in goats. Examinations were performed using transrectal ultrasound equipped with a linear transducer of double frequency. Fetuses were identified as male when the GT was next to the umbilical cord and female when the GT was next to the tail. The average time of GT migration in ewes (41.3 +/- 3.1 days) was shorter (P < 0.05) than in goats (47.2 +/- 2.3 days)? In goats, the average time of GT migration of Saanen fetuses was later (P < 0.05) than in fetuses of other breeds, with no difference in the average time of GT migration between male (46.9 +/- 2.2) and female fetuses (47.4 +/- 2.4). In ewes, the average time of GT migration did not differ (P > 0.05) among breeds and sexes. In goat and sheep, no difference was noticed in the accuracy of fetal sexing between males and females (P > 0.05). The results show that fetal sexing in ewes must be done earlier than in goats, fetal sexing in Saanen goats must be performed later, and fetal sex does not influence the time of GT migration in either of the two species.

Despite their profound importance in the development of cancer, the extracellular cues that target cell invasion through basement membrane barriers remain poorly understood. A central obstacle has been the difficulty of studying the interactions between invading cells and basement membranes in vivo. Using the genetically and visually tractable model of Caenorhabditis elegans anchor cell (AC) invasion, we show that UNC-6 (netrin) signalling, a pathway not previously implicated in controlling cell invasion in vivo, is a key regulator of this process. Site of action studies reveal that before invasion, localized UNC-6 secretion directs its receptor, UNC-40, to the plasma membrane of the AC, in contact with the basement membrane. There, UNC-40 polarizes a specialized invasive membrane domain through the enrichment of actin regulators, F-actin and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Cell ablation experiments indicate that UNC-6 promotes the formation of invasive protrusions from the AC that break down the basement membrane in response to a subsequent vulval cue. Together, these results characterize an invasive membrane domain in vivo, and reveal a role for UNC-6 (netrin) in polarizing this domain towards its basement membrane target.

The mammalian female reproductive tract develops from the Mullerian ducts which differentiate, in a cranial to caudal direction, into oviducts, uterine horns, cervix and the anterior vagina. The developmental processes taking place during this organogenesis are notably under the control of steroid hormones, such as members of the Wnt and Hox families, which regulate key developmental genes. At later stages, steroid hormones also participate in the development of the female genital tract. Chemical compounds homologous to steroids can thus act as agonists or antagonists in fetuses exposed to them. These so-called endocrine disruptors are nowadays found in increasing amounts in the environment and may therefore have a particular impact on such developing organs. Epidemiological studies have revealed that endocrine disruptors have had drastic effects on female health and fertility during the last decades. Furthermore, these adverse effects might be transmitted to subsequent generations through epigenetic modifications. Given the potential hazard of inherited epigenetic marks altering reproduction and/or human health, such molecular mechanisms must be urgently investigated. This review aims to summarize the cellular and molecular mechanisms involved in female genital tract development, to highlight key genes involved in this process and to present epigenetic mechanisms triggered by endocrine disruptors and their consequences in regard to female reproductive tract development.