Primary Amenorrhea Due to Anatomical Abnormalities of the Reproductive Tract: Molecular Insight.

Congenital anomalies of the female reproductive tract that present with primary amenorrhea involve Müllerian aplasia, also known as Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), and cervical and vaginal anomalies that completely obstruct the reproductive tract. Karyotype abnormalities do not exclude the diagnosis of MRKHS. Familial cases of Müllerian anomalies and associated malformations of the urinary and skeletal systems strongly suggest a complex genetic etiology, but so far, the molecular mechanism in the vast majority of cases remains unknown. Primary amenorrhea may also be the first presentation of complete androgen insensitivity syndrome, steroid 5α-reductase type 2 deficiency, 17ß-hydroxysteroid dehydrogenase type 3 deficiency, and Leydig cells hypoplasia type 1; therefore, these disorders should be considered in the differential diagnosis of the congenital absence of the uterus and vagina. The molecular diagnosis in the majority of these cases can be established.

The development of the human vaginal fornix and the portio cervicis.

INTRODUCTION: One of the transitional zones of the human body is situated in the cervix uteri. The developmental differentiation of epithelial and stromal characteristics in such a region is of high clinical interest. However, few studies have focused on the development of this region, and information in anatomical and clinical textbooks is limited. We therefore examined the development of the human vaginal fornix and the cervix uteri during prenatal development. MATERIALS AND METHODS: We examined 29 female embryos and fetuses between 20 and 34 weeks and two newborns using histology and immunohistochemistry. RESULTS: The characteristic shape of the portiocervicis and the vaginal fornix first became visible in mid-term fetuses because of the different muscular coats and of an uncategorized Müllerian-derived epithelium, which was rapidly replaced by a multilayered squamous epithelium. Only thereafter, in older fetuses, were there organogenetic differentiation of the epithelia and the underlying stroma of the cervical canal. UGS-derived p63/CK17-positive cells could be identified as precursor cells for the squamous epithelium, and Müllerian-derived CK7-positive cells for the columnar-type epithelium. Both cell types and different stromal zones were already present in a prenatal transformation zone. Initial functional differentiation could be observed in perinatal stages. CONCLUSIONS: Our results on prenatal human development strongly support the view that two different cell lineages meet at the transitional zone of the cervix uteri and that these lineages depend on alternative signals from the underlying stromal compartment.

Vía de finalización en pacientes con segunda inducción al trabajo de parto en el Hospital Nacional prof. A. Posadas / Postterm pregnancy in patients with second labour induction - Author's experience

The labour induction is an intervention to initiate artificially the uterine contractions to produce the effacement and dilatation of the uterine cervix until the child-birth is achieved. It is indicated when the benefit of the termination of the pregnancy for the mother and the child is greater than its continuation. It is perfored in more or less the 20 % of the women. In our institution the rate oscillates in around the 9 % of the cases. It is understand as an successful induction the termination of the labour through the vaginal delivery. The methods for labour induction more commonly used at present are mechanical and pharmacological. Between the first group we can find the Hamilton maneuver and the amniotomy. And between the pharmacologicals we find the oxytocine. These elements are considered in the article

The potential perinatal origin of placentation disorders in the young primigravida.

The fetus is exposed to high plasma concentrations of unbound estrogens and progesterone throughout pregnancy. However, secretory or decidual changes in the fetal uterus occur relatively infrequently before birth, suggesting a variable endometrial progesterone response at the time of birth. Arguably, partial progesterone resistance that persists into adolescent years may compromise the physiological transformation of the spiral arteries and predispose for defective placentation in the case of pregnancy. Decidualization of the endometrial stromal compartment and junctional zone myometrium precedes trophoblast invasion. It represents the first step in the process of spiral artery remodeling needed to establish effective uteroplacental blood flow by midpregnancy. The major obstetric syndromes caused by impaired placental bed spiral artery remodeling are prevalent in teenage pregnancies, including preeclampsia, fetal growth restriction, and spontaneous preterm labor. Preconditioning of the uterus in response to cyclic menstruation during adolescence may be critical to achieve full uterine responsiveness to hormonal cues. Understanding the mechanisms of functional maturation of the uterus during the early reproductive years may yield novel insights into the major obstetric syndromes.

[EMBRYONIC SOURCES OF "RESERVE CELLS" DEVELOPMENT IN THE EPITHELIAL LINING OF THE CERVIX].

Using general histological and immunohistochemical methods, the sources of "reserve cells" of the epithelial lining of the uterus and vagina were studied on the material obtained from human embryos and fetuses. From 13th to 20th week of fetal development, the epithelial lining of the cervix was formed with the participation of the urogenital sinus (UGS). The cells of the latter interacted with the coelomic epithelial cells of the paramesonephric ducts (PMD). After 25th week, UGS cells were dispersed along the length of the cervix, lying on the basement membrane beneath the columnar epithelial cells. It is suggested that epitheliocytes of UGS are the source of the "reserve cells". Taking into account the tissue nature of the "reserve cell" it is expedient to determine them as mesonephroblasts. Cells are present in the cervical epithelium as a concomitant determined cellular differon.

The developmental origin of cervical and vaginal epithelium and their clinical consequences: a systematic review.

OBJECTIVE: Studies on the development of the embryological and fetal development of the cervix and the vagina are rare and mostly go back to the first decades of the last century. The aims of this review were to present the latest knowledge concerning the developmental origin of cervical and vaginal epithelium and to point out new results in the context of different clinical findings. MATERIALS AND METHODS: Relevant studies published between 1910 and 2013 were identified via PubMed, MEDLINE, OVID, Web of Science, and EMBASE. The reference lists of retrieved articles were reviewed to locate additional articles. Each abstract was reviewed, and the appropriate publications were obtained and reviewed as well. A total of 33 articles and 8 book chapters were selected for citation in this review. RESULTS: New objective findings clearly show that human prenatal epithelialization of the cervix and vagina results in 3 morphogenetically determined units: (i) the Müllerian columnar epithelium of the endocervix, (ii) the Müllerian squamous epithelium of the ectocervix and the upper vagina, and (iii) the vaginal squamous epithelium of the lower vagina. CONCLUSIONS: These results are of high clinical relevance and may provide new insight into the histogenesis of ectopy, vaginal adenosis, and the congenital transformation zone. They should be added to the explanations in gynecological, colposcopical, and gynecopathological textbooks.

Viable offspring after successful non-surgical embryo transfer in goats / Nascimento de fetos viáveis após transferência de embriões não-cirúrgica em caprinos

O objetivo do presente estudo foi avaliar a viabilidade da técnica de transferência não cirúrgica em cabras. Quatro cabras não-lactantes pluríparas da raça Toggenburg foram utilizadas como receptoras de embriões, sendo que duas receberam um embriões e duas receberam dois embriões coletados não cirurgicamente cabras doadoras. Os corpos lúteos das receptoras foram detectados um dia antes da transferência de embriões por ultrassonografia transretal. Uma seringa de 5mL contendo 2mL de meio holding foi acoplada em um cateter tomcat, no qual os embriões foram aspirados em uma coluna central a duas outras colunas. Um espéculo Colin número 2 foi inserido na vulva e na vagina, e com o uso de uma fonte de luz, a cerviz foi localizada e imobilizada com uma pinça de Allis. Um cateter uretral número seis acoplado a um mandril e lubrificado com meio PBS foi inserido na cérvix, e assim os aneis cervicais foram gradualmente transpostos. Após perder a resistência, o cateter uretral foi movido lateralmente para o corno uterino desejado. O mandril e a pinça de Allis foram retirados e o conjunto seringa e tomcat foi acoplado ao cateter uretral e o conteúdo injetado no corno uterino ipsilateral ao corpo lúteo com posterior retirada do cateter. Cabras que ovularam em apenas um ovário foram usadas para testar a eficiência da deposição do embrião. O tempo gasto entre a inserção do espéculo e a sua remoção foi inferior a três minutos. O tempo para transpor a cérvix foi inferior a um minuto. A ultrassonografia revelou a deposição de líquido no corno desejado. Receptoras que receberam dois embriões tornaram-se gestantes e pariram três crias. Estes primeiros resultados encorajam a técnica e demonstram que a transferência de embriões em caprinos pode ser feita totalmente por procedimentos não cirúrgicos...

Association between developmental steps in the organogenesis of the uterine cervix and locoregional progression of cervical cancer: a prospective clinicopathological analysis.

BACKGROUND: Our previous work provided evidence that early cervical cancer is locally confined to the Müllerian compartment that develops in women from the embryonic paramesonephric-mesonephric complex. We aimed to investigate if the concept of tumour permeation within ontogenetic domains is also valid for tumour progression and advanced disease. METHODS: Starting from Carnegie stage 13, four successive steps in the organogenesis of the human uterine cervix were defined and an ontogenetic staging system for cervical cancer based on organ development was described. Histopathological and clinical data of patients with cervical cancer FIGO stages IB-IVA were raised prospectively from Oct 16, 1999, until Dec 20, 2012, and from March 8, 2000, until April 4, 2013, for two surgical trials of ontogenetic compartment resection without adjuvant radiation at the University of Leipzig (total or extended mesometrial resection [TMMR or EMMR]; and [laterally] extended endopelvic resection [LEER]). The primary endpoints of these trials were pathological resection state and locoregional tumour control. Patients who underwent TMMR and EMMR had follow-up assessment every 3-6 months for 5 years, and yearly thereafter. Patients who had (L)EER, every 3-6 months for 10 years, and yearly thereafter. By analysing the presence of disease within the classified tissues and disease outcome in these patients, and by examining relapse patterns, we were able to observe whether surgical excision within developmental compartments was sufficient for disease control. Survival curves were compared using the log-rank test. The effect of ontogenetic tumour stage and pathological tumour stage on overall survival was assessed by Cox proportional hazard models. The trials are registered as an ongoing observational monocentric study at the University of Leipzig Cancer Centre (ULCC012-13-28012013). FINDINGS: 367 patients were included in our analysis. Staged organogenesis of the uterine cervix and progressive local growth of cervical carcinoma occur in the same tissue domains. The neoplasm originating in the uterine cervix, ontogenetic tumour stage 1 (oT1, n=217), permeates successively during its malignant progression the tissues developed from the Müllerian compartment (oT2, n=101), the genital metacompartment (oT3, n=38), and the urogenitorectal metacompartment (oT4, n=11). Ontogenetic staging, when comparing patients with oT1 and oT2 disease to those with oT3 and oT4 disease (hazard ratio 5·9, 95% CI 2·2-15·5; p=0·00036) was a better prognostic indicator for survival than pathological staging when comparing pT1b and pT2a with pT2b and pT4 disease (2·0, 95% CI 0·7-5·5; p=0·170). Resection of the stage-related ontogenetically specified tissue domains and their associated regional lymphoid tissues achieved an R0 resection in 363 (99%) of 367 patients and locoregional tumour control at 5 years was 94% (95% CI 92-97). 13 patients had grade 3 or 4 adverse events, the majority of which were urinary (10, 77%). INTERPRETATION: Cervical cancer infiltrates the adult tissues established during ontogeny, pursuing the developmental steps in retrograde sequence. Clinical translation of these insights into ontogenetic tumour staging and compartment resection holds the potential to improve prognostic assessment and curative treatment. FUNDING: University of Leipzig and Leipzig School of Radical Pelvic Surgery.

Pelvic exenteration for recurrent squamous cell carcinoma of the pelvic organs arising from the cloaca--a single institution's experience over 16 years.

AIM: Minimal data are available on the role of pelvic exenteration in patients with recurrent squamous cell carcinoma (SCC) of the pelvic organs. This study aimed to highlight our experience of pelvic exenteration in patients with recurrent and re-recurrent SCC of the pelvic organs. METHOD: A retrospective review of all patients who underwent pelvic exenteration for recurrent SCC of the pelvic organs arising from the embryological cloaca from 1994 to 2010 was performed. RESULTS: Twenty-four patients (median age 59, range, 27-79 years) underwent pelvic exenteration for recurrent SCC of the anus (18), cervix and upper vagina (2), lower vagina (1) and the vulva (3). Nine patients with anal SCC had undergone abdominoperineal excision prior to pelvic exenteration. Ten (41.7%) patients underwent a complete pelvic exenteration procedure, while sacrectomy was performed in 13 (54.2%) patients. There was no 30-day inpatient mortality. An R0 resection was achieved in 15 (62.5%) patients. Three (12.5%) had R1 resections while 6 (25%) had R2 resections. In the 15 patients with an R0 resection, 7 (46.7%) developed metastatic disease at a median of 18 (range 10-131) months. After a median follow-up of 26 (range 4-169) months, 1- and 2-year overall survival rates were 64% [95% confidence interval (CI), 44-84%] and 57% (95% CI 35-79%), respectively. CONCLUSION: Pelvic exenteration for recurrent SCC of the cloaca is safe and feasible even after previous salvage surgery. An R0 resection can be achieved in 62.5% of the patients with reasonable early survival though less than published recurrent rectal cancer studies.

A novel blueprint for 'top down' differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia.

The cervical squamocolumnar (SC) junction is the site of a recently discovered 'embryonic' cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodelling and neoplasia is unclear. In the present study, we analysed the SC junction immunophenotype during pre- and post-natal human and mouse development and in the adult, processes of metaplastic evolution of the SC junction, microglandular change, and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the SC junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic/SC junction cells gave rise to subjacent metaplastic basal/reserve cells with a switch from the SC junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or 'top down' differentiation. A similar pattern was noted in high-grade squamous intraepithelial lesions (HSILs), suggesting that HPV infection of the cuboidal SC junction cells initiated outgrowth of basally-oriented neoplastic progeny. The progressive loss of the embryonic/SC junction markers occurred with 'top down' differentiation during development, remodelling, and early neoplasia. Interestingly, most low-grade SILs were SC junction-negative, implying infection of metaplastic progeny rather than the original SC junction cells. This proposed model of 'top down' differentiation resolves the mystery of how SC junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the SC junction is uniquely susceptible to carcinogenic HPV infection.

Surgical methods in the treatment of congenital anomalies of the uterine cervix.

PURPOSE OF REVIEW: Cervical agenesis is an extremely rare congenital anomaly of the female reproductive tract. There are many anatomical forms that constitute this type of cervical abnormality and the literature is replete with attempts to surgically restore a patent outflow tract and preserve fertility in these patients. There are no carefully designed cohort or randomized trials to support a best surgical practice; past reports are descriptive only. RECENT FINDINGS: Of late, there has been renewed interest in the surgical treatment of cervical dysgenesis with techniques both through laparotomy with hysterotomy and more recently, minimally invasive approaches, which have attempted to restore a patent outflow tract without perineal dissection or graft harvesting in an attempt to avoid uterovaginal scarring if further surgery is necessary. To maintain consistency in the field of surgical reconstruction of the female reproductive tract, there has been a call for streamlined classifications of the anatomical abnormalities observed to better compare patient findings and the outcome of their surgical reconstruction in the literature. SUMMARY: The authors discuss the embryological development of this rare reproductive tract abnormality and have proposed a systematic surgical strategy for each anatomic finding. Ultimately, counseling patients on the best surgical approach requires a discussion on the potential postoperative complications, the degree of cervical abnormality, and the patient's desired treatment outcome. Whether the patient desires definitive treatment with a hysterectomy to avoid the risk of further surgery or, when anatomically appropriate, she wants to pursue a patent outflow tract and the possibility of future childbearing, evidence-based medicine must become the source for surgical strategies.

Normal and abnormal epithelial differentiation in the female reproductive tract.

In mammals, the female reproductive tract (FRT) develops from a pair of paramesonephric or Müllerian ducts (MDs), which arise from coelomic epithelial cells of mesodermal origin. During development, the MDs undergo a dynamic morphogenetic transformation from simple tubes consisting of homogeneous epithelium and surrounding mesenchyme into several distinct organs namely the oviduct, uterus, cervix and vagina. Following the formation of anatomically distinctive organs, the uniform MD epithelium (MDE) differentiates into diverse epithelial cell types with unique morphology and functions in each organ. Classic tissue recombination studies, in which the epithelium and mesenchyme isolated from the newborn mouse FRT were recombined, have established that the organ specific epithelial cell fate of MDE is dictated by the underlying mesenchyme. The tissue recombination studies have also demonstrated that there is a narrow developmental window for the epithelial cell fate determination in MD-derived organs. Accordingly, the developmental plasticity of epithelial cells is mostly lost in mature FRT. If the signaling that controls epithelial differentiation is disrupted at the critical developmental stage, the cell fate of MD-derived epithelial tissues will be permanently altered and can result in epithelial lesions in adult life. A disruption of signaling that maintains epithelial cell fate can also cause epithelial lesions in the FRT. In this review, the pathogenesis of cervical/vaginal adenoses and uterine squamous metaplasia is discussed as examples of such incidences.

Reserve cells in human uterine cervical epithelium are derived from müllerian epithelium at midgestational age.

The role of endocervical reserve cells in squamous metaplasia and neoplasia is still debated. Their origin in the cervix is open to speculation and it is unclear how they are targeted during carcinogenesis. To further understand the primary characteristics of reserve cells, we phenotyped them in the developing human cervix. In 13 perinatal autopsies of fetuses between 16 and 40 weeks of gestation, the human fetal cervix was evaluated in serial sections. Immunostaining comprised a panel of antibodies for cytokeratins, p63, and bcl-2; then, the sections were stained with Alcian blue and periodic acid-Schiff before and after diastase treatment. Reserve cells are first identified at approximately 20 weeks of gestation. They are first noted under müllerian-type columnar cells lining the developing uterine cavity. There is considerable overlap in the expression profiles of müllerian cells and reserve cells for p63, bcl-2, and cytokeratins 5, 8, and 18 at this stage of development, with increasing gestational age expression localized to respective cell compartments. Eventually, the phenotype of these cells correspond fully with that described for adult reserve cells and endocervical cells. Müllerian epithelial cells are the stem cell for endocervical reserve cells and endocervical columnar cells. They have the capacity to transform into both endocervical columnar and squamous-type epithelium in the endocervix during early cervical development.

Double vagina and cervix communicating bilaterally with a single uterine cavity: report of a case with an unusual congenital uterine malformation.

BACKGROUND: The existence of a longitudinal vaginal septum with double cervix communicating bilaterally with a nonseptate uterine body and normal adnexa is an unusual müllerian anomaly. CASE: A 43-year-old woman presented with menorrhagia and duplication of the cervix and vagina. Afibromatous uterus was suggested by clinical examination and confirmed by ultrasonography. The patient underwent total abdominal hysterectomy with bilateral salpingooophorectomy. The surgical specimen revealed a fibromatous uterus with double cervix communicating bilaterally with a nonseptate uterine body; both adnexa were normal. CONCLUSION: This rare müllerian anomaly is inconsistent with the classical embryologic theory of caudal to cranial müllerian development but supports the alternative embryologic hypothesis suggested by Müller et al, according to which fusion and absorption begin at the isthmus and proceed simultaneously in both the cranial and caudal directions.

Association between the mesenchymal compartment of uterovaginal organogenesis and local tumour spread in stage IB-IIB cervical carcinoma: a prospective study.

BACKGROUND: Macroscopic, microscopic, and occult local tumour spread might be restricted to a permissive territory related to the morphogenesis of the tissue or organ from which the tumour originates. We aimed to define such a morphogenetic unit in Müllerian development, and to assess the role of total mesometrial resection in the treatment of patients with stage IB-IIB cervical carcinoma. METHODS: We analysed uterovaginal development in serial sections of female human embryos and fetuses, and defined the distal Müllerian morphogenetic unit from the Müllerian mesenchyme. We assessed prospectively the histopathological and clinical findings from patients who underwent total mesometrial resection-modified surgery for stage IB-IIB cervical carcinoma that aims to remove the uterus, proximal vagina, and extracervical mesenchyme within the borders of the distal Müllerian morphogenetic unit. FINDINGS: The spatial extension of the Müllerian mesenchyme, its vascularisation, and its innervation during early uterovaginal organogenesis determine a tissue territory that can be followed during fetal development and identified in women as a morphogenetic unit. 105 of 106 patients who had total mesometrial resection, 63 of whom were classed as high risk, had microscopically tumour-free resection margins (ie, R0). 48 (96%) of 50 patients had pelvic recurrence-free survival at 3 years (95% CI 92-100) without adjuvant radiotherapy. INTERPRETATION: Radical en-bloc resection of a topographically defined anatomical territory derived from common precursor tissue leads to local tumour control, preservation of autonomic nerves, and a reduced need for adjuvant radiotherapy.

[Subdivision of the female pelvic connective tissue: new interpretation based on morphological and embryological studies]. / Gliederung des Bindegewebes im weiblichen Becken Neue Konzeption aufgrund morphologisch-embryologischer Untersuchungen.

As we suppose that the knowledge of the prenatal development within the pelvic floor is necessary to understand the subdivision of the pelvic connective tissue we studied transparent sections through the untouched pelvis of fetuses and newborn. We compared them with those of adults and included modern imaging techniques. Our results show, that the classical concept concerning the subdivision of the pelvic connective tissue needs to be revised.

Cytologic features of ciliated adenocarcinoma of the cervix: a case report.

BACKGROUND: Ciliation is a normal finding in the endometrium, fallopian tubes and cervix. Because cilia are characteristically lost when malignant tumors arise at these sites, the detection of cilia on light microscopy is frequently used to support a benign diagnosis. Ciliated carcinomas of müllerian duct origin, however, do occur, albeit rarely, and can pose a potential diagnostic difficulty in cytologic specimens. CASE: A woman with a histologically confirmed ciliated adenocarcinoma of the cervix had prior liquid-based cervical cytology showing atypical, ciliated glandular cells that initially raised the diagnostic consideration of tubal metaplasia. A concurrent biopsy, however, revealed focally ciliated adenocarcinoma of the cervix. CONCLUSION: Awareness of the ciliated variant of adenocarcinoma of the cervix is important to avoid overreliance on ciliation as a definitive feature of benignity in cervical cytologic specimens.

Expression of growth hormone secretagogue receptor type 1a, the functional ghrelin receptor, in human ovarian surface epithelium, mullerian duct derivatives, and ovarian tumors.

Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), is a newly identified, ubiquitously expressed molecule that has been involved in a wide array of endocrine and nonendocrine functions, including cell proliferation. In this context, our group recently reported the expression of ghrelin and its functional receptor, the GHS-R type 1a, in the human ovary and testis as well as several testicular tumors. Ovarian malignancies, however, remain unexplored. Notably, a vast majority of ovarian tumors derive from the surface epithelium, which originates from the celomic epithelium. Considering the proven expression of ghrelin in the human ovary, and its reported effects in the proliferative activity of different cancer cell lines, we aimed at evaluating whether the ovarian surface epithelium as well as related reproductive structures and tumors are potential targets of ghrelin. To this end, expression of GHS-R1a was analyzed by immunohistochemistry in a panel of normal, metaplastic, and neoplastic tissues. Uniform GHS-R1a immunostaining was detected throughout the ovarian surface epithelium. Likewise, ciliated cells within the fallopian tube epithelium showed strong GHS-R1a expression. In contrast, other celomic derivatives, such as endometrium and endocervix, were negative for GHS-R1a immunoreactivity. In keeping with data from normal tissues, inclusion cysts from the surface epithelium expressed GHS-R1a. Similarly, benign serous tumors resembling fallopian tube epithelium were also positive, whereas serous cystadenocarcinomas showed GHS-R1a expression only in highly differentiated specimens. In contrast, other neoplasms, such as mucinous cystadenomas and cystadenocarcinomas, endometrioid tumors, clear cell carcinomas, and Brenner tumors, did not express GHS-R1a. In conclusion, our results demonstrate that the ovarian surface epithelium and related tumors are potential targets for systemic or locally produced ghrelin because they express the functional type 1a GHS-R. Considering the relevant role of the ovarian surface epithelium in key physiological events (such as ovulation) and neoplastic transformation of the ovary, the potential actions of ghrelin in those phenomena merit further investigation.