Endometriosis origin from primordial germ cells

Endometriosis is defined by the presence of endometrial ectopia. Multiple hypotheses have been postulated to explain the etiology of endometriosis to understand various clinical evidences. The etiology of endometriosis is still unclear.The primary question to understanding the etiology of endometrial ectopia (endometriosis) is determining the origin of eutopic (normally cited) endometrium.According to the new theory, primordial germ cells migrate from hypoblast (yolk sac close to the allantois) to the gonadal ridges. The gonadal ridges which composed of primordial germ cells derive to the: eutopic endometrium, ovary, ovarian ligament and ligamentum teres uteri.There are 2 principal processes in uterine organogenesis: the intersection of gonadal ridges with mesonephral ducts to form the uterine folds with an endometrial cavity and the fusion of the both uterine folds together to form the unicavital (normal) uterus. In the uterine folds there are closer cell-to-cell communications, polypotential germ cells differentiate and grow into myometrium and endometrial layers.Some of the polypotential germ cells fail to reach the ridges and stay in the peritoneal cavity, where they may be transforming into external endometrial heterotopies.The main insight in the etiology of endometriosis is polypotential germ cells origin, which may explain its potency, pathogenesis and expansion.     

Periductal and matrix glycosaminoglycans in rat Mullerian duct development and regression

Gonadal ridges containing Mullerian and Wolffian ducts were removed from rat embryos from Days 14 through 16 of gestation and their production of glycoprotein, hyaluronate, and sulfated glycosaminoglycans examined. Autoradiographic, histochemical, and biochemical studies indicate that the periductal zone contains hyaluronate and sulfated glycosaminoglycans, that these matrix constituents are degraded during development, and that the proportions of glycosaminoglycans accumulated by isolated female gonadal ridges in vitro can be altered by the addition of Mullerian inhibiting substance to the culture medium. When the Mullerian duct regressed there was an unexpected persistence of labeled glucosamine derivatives in cells in the mesenchymal cell space suggesting that some such cells are dissociated ductal epithelial cells which have transformed into mesenchyme.     

Mayer-Rokitansky-Kuster-Hauser syndrome type II: A rare case

Mayer-Rokitansky-Kuster-Hauser (MRKH) is a malformation complex comprising absent vagina and absent or rudimentary uterus. MRKH syndrome may be attributed to an initial affection of the intermediate mesoderm consequently leading (by the end of the 4^th week of fetal life) to an alteration of the blastema of the cervicothoracicsomites and the pronephricducts. These latter subsequently induce the differentiation of the mesonephric and then the Wolffian and Mullerian ducts. There are very sparse such cases reported. We present a case of type II MRKH or Mullerian renal cervical somite association (i.e., Mullerian duct aplasia, renal dysplasia, and cervical somite anomalies).     

A mesenchymal perspective of Müllerian duct differentiation and regression in Amhr2-lacZ mice

The Müllerian ducts give rise to the female reproductive tract, including the Fallopian tubes, uterus, cervix, and anterior vagina. In male embryos, the Müllerian ducts regress, preventing the formation of female organs. We introduced the bacterial lacZ gene, encoding beta-galactosidase (beta-gal), into the AMHR-II locus (Amhr2) by gene targeting in mouse embryonic stem (ES) cells to mark Müllerian duct differentiation and regression. We show that Amhr2-lacZ heterozygotes express beta-gal activity in an Amhr2-specific pattern. In the gonads, beta-gal activity was detected in Sertoli cells of the testes from 2 weeks after birth, and fetal ovaries and granulosa cells of the adult ovary. beta-gal activity was first detected in the rostral mesenchyme of the Müllerian ducts at 12.5 days post coitus (dpc) in both sexes but soon thereafter expression was found along the entire length of the Müllerian ducts with higher levels initially found in males. In females, beta-gal activity was restricted to one side of the ductal mesoepithelium, whereas in males beta-gal expression encircled the duct. beta-gal activity was also detected in the coelomic epithelium at 13.5 and 14.5 dpc. In male embryos, mesenchymal beta-gal activity permitted the visualization of the temporal and spatial pattern of Müllerian duct regression. This pattern was similar to that observed using a Müllerian duct mesoepithelium lacZ reporter, indicating a coordinated loss of Müllerian duct mesoepithelium and Amhr2-expressing mesenchyme.     

Human müllerian inhibitory factor messenger ribonucleic acid is hormonally regulated in the fetal testis and in adult granulosa cells

The regression of the Müllerian ducts (the embryologic precursor of uterus, vagina, and Fallopian tubes) in the male fetus is caused by Müllerian inhibitory factor (MIF), a glycoprotein produced by fetal Sertoli cells. Although this Müllerian duct involution is complete before midgestation, the amount of MIF mRNA did not vary among 25 human fetal testis samples from 13 to 25.8 weeks of gestation. In cultured 20-week human testis cells, cAMP increased MIF mRNA 8.3-fold, but the human gonadotropins FSH and CG had no effect. In cultured adult human granulosa cells, CG and cAMP increased MIF mRNA accumulation to 430% and 890%, respectively, but FSH had no effect. The expression and hormonal regulation of MIF mRNA in midgestation testes and in adult granulosa cells indicate that MIF has physiological roles in the human gonad other than Müllerian duct regression.     

Ultrastructure of genital system ducts of Diphyllobothrium latum (Cestoda:Pseudophyllidae): the ducts of the female reproductive system

The components of the female reproductive system of Diphyllobothrium latum, including ovary, ovicapt, oviduct, vitelline ducts, vitelline reservoir, vagina, seminal receptacle, ootype with unicellular Mehlis's gland, ootype-uterine duct and uterus were observed with the electron microscope. The epithelium of the female reproductive system ducts consists of a nucleate syncytial layer. Structural differences in apical surface of the ducts, the number of nuclei and organoids in syncytial layer as well as the number of underlaid muscles were revealed. The regional differentiations of the uterus wall were registered. The middle and distal region of uterus was covered with microtriches. The filamentous microtriches were observed in apical surface of vagina. The epithelium of seminal receptacle and distal region of uterus were underlaided by the powerful muscle layers. The fertilization canal was revealed. It was shown that the formation of egg shells implemented by the deposit of vitelline globules in their surface in the ootype-uterine duct. Structural and functional differences of different parts of female apparatus in various groups of cestodes are conditioned by species biology.     

Genetics and molecular pathology of anti-Mullerian hormone and its receptor

Anti-müllerian hormone (AMH), a glycoprotein produced by immature Sertoli cells, is responsible in male fetuses for regression of müllerian ducts, the anlagen of Fallopian tubes and uterus in females. AMH binds to a specific type II serine-threonine kinase transmembrane receptor (AMHR-II). A known pathology of AMH and its receptor is the persistent müllerian ducts syndrome (PMDS), a peculiar case of male pseudohermaphroditism, presenting with retention of tubes and uterus in otherwise normally virilized boys, and transmitted with an autosomic recessive mode. Genetic studies on 76 families of patients allowed identification of AMH gene mutations in 45%, and AMHR-II gene mutations in 39% (including a 27 bases deletion in half of the latter). In 15% mutation of none of the two genes was detected, thus mutations are expected in genes coding for other factors of the AMH transduction cascade.     

Gamma-aminobutyric acid in the genital tract of the rat during the oestrous cycle

The highest values of gamma-aminobutyric acid (GABA) in the genital tract of the rat at different stages of the oestrous cycle were found in the oviduct (3.5-7 micrograms/mg protein) and the lowest in the ovary (50-100 ng/mg protein). The values for uterus and vagina ranged between 80 and 150 ng/mg protein. GABA (10-30 ng/microliter) was also found in fluid in the ovarian bursa. At 11:00 h, on the day of oestrus, GABA content increased in the ovaries but values in the oviducts were maximal at 11:00 h on the day of pro-oestrus. Variations in GABA content of the vagina were also found. Uterine cervix or uterine horn showed no changes during the oestrous cycle. The GABA content was not uniform throughout the oviduct: the highest values were found in the portion next to the ovary. At 10 days after removal of the right oviduct, GABA values in the ovary and ovarian bursa fluid decreased on the operated side. At 1 month after surgery, the values in ovary were normal but the values in ovarian bursa fluid were still low, suggesting that the source of ovarian GABA was not the oviduct. The variations observed in the present paper suggest an involvement of GABA in reproductive physiology.     

A complex intersex condition in a Holstein calf

A case of disrupted embryonic development of the genital tract in a newborn Holstein calf is described. The physical examination of the calf evidenced several abnormalities, like atresia ani, rudimentary external genitalia and caudal vertebral agenesis. On necropsy, the excised genitalia consisted of bilateral streak gonads, apparently normal uterine tubes, a fluid-filled uterus, a long vagina and a very narrow clitoris-like structure covered with a discrete skin-fold. The urinary tract seemed normal and the urethra's opening was at the vestibule-vaginal junction. A cytogenetic analysis was requested. Karyotype revealed the existence of Y chromosome material in the two X chromosomes. However, the search for the sex-determining region Y (SRY) showed that this was an apparently absent gene. The histological examination of the gonads revealed the existence of ovarian dysplasia. Uterine sections evidenced the absence of the uterine epithelium, with only sporadic caruncles. Under microscopic examination, the uterine tubes and vagina structure was normal. The external genitalia sections revealed the existence of a skin-fold covering an erectile structure surrounding the urethra, a structure more similar to a penis than to a clitoris. This is an unusual situation of gonadal dysplasia combined with genital tract anomalies in cattle, probably associated to a genetic defect.     

Differences in prolactin receptor (PRLR) in mouse and human fallopian tubes: evidence for multiple regulatory mechanisms controlling PRLR isoform expression in mice

The anterior pituitary-derived hormone prolactin (PRL) signals through the PRL receptor (PRLR) and is important for female reproductive function in mammals. In contrast to the extensive studies of PRLR expression and regulation in human and mouse ovary and uterus, the mechanisms controlling the regulation of PRLR isoform expression in the fallopian tube are poorly understood. Because dynamic interaction of hormonal signaling in gonadal tissue and the pituitary or in gonadal tissues themselves in mammals suggests endocrine or paracrine regulation of PRLR expression, we questioned whether differential regulation of PRLR isoforms by PRL ovarian-derived estrogen (E(2)) and progesterone (P(4)) exists in the fallopian tube and pituitary of prepubertal female mice. Western blot analysis showed distinct molecular separation of PRLR isoforms in mouse and human fallopian tubes, and cellular localization was found in mouse and human tubal epithelia but not in mouse tubal smooth muscle cells. These data support the concept of an isoform- and cell type-specific expression of PRLR in human and mouse fallopian tubes. Moreover, expression of the long form of PRLR decreased after PRL treatment and increased after blockage of endogenous PRL secretion by bromocriptine (an inhibitor of PRL secretion) in a time-dependent manner in mouse fallopian tube. The opposite regulation was observed in the pituitary. Treatment with exogenous E(2) or P(4) led to changes in PRLR expression in the fallopian tube similar to those of PRL treatment. However, E(2) and P(4) did not affect PRLR expression in the pituitary. Estrogen had no effect on the long form of PRLR expression, whereas P(4) regulated the long form of PRLR in the fallopian tube, as did PRL. Taken together, the data from our comparative study provide evidence that PRLR can be regulated by an interplay of two different mechanisms, PRL or ovarian steroid hormones independently or in combination in a tissue-specific manner. Furthermore, we found that ovarian steroid hormones selectively suppress the expression of PRLR isoforms in mouse fallopian tubes. These findings may contribute to our understanding of the mechanisms controlling PRLR isoform expression in the fallopian tube (in addition to ovary and uterus), with implications for female reproduction.     

The involvement of hypophyseal‐gonadal and hypophyseal‐adrenal axes in arsenic‐mediated ovarian and uterine toxicity: Modulation by hCG

This study evaluated the involvement of hypophyseal‐gonadal and hypophyseal‐adrenal axes as a possible mechanism of sodium arsenite toxicity in ovary and uterus by the coadministration of hCG. Subchronic treatment of 0.4 ppm of sodium arsenite/(100 g body weight day) via drinking water for seven estrous cycles significantly suppressed the plasma levels of leutinizing hormone, follicle‐stimulating hormone, and estradiol along with sluggish ovarian activities of Δ⁵,3β‐hydroxysteroid dehydrogenase and 17β‐hydroxysteroid dehydrogenase followed by a reduction in gonadal tissue peroxidase activities in mature female rats at diestrous phase. Noticeable weight loss of the ovary and uterus along with prolonged diestrous phase and increased deposition of arsenic in the plasma and in these reproductive organs were also demonstrated following the ingestion of arsenic. Follicular atresia and thinning of the uterine luminal diameter were evident after sodium arsenite treatment. Effective protection of gonadal weight loss, suppressed ovarian steroidogenesis, and altered ovarian and uterine peroxidase activities were noticed when 1.0 IU hCG/(100 g body weight day) is given in arsenic‐intoxicated rats. Normal estrous cyclicity was restored toward the control level after hCG coadministration, though the elimination of elementary arsenic from the plasma and gonadal tissues was impossible. A significant recovery in the restoration of ovarian and uterine histoarchitecture was prominent after hCG treatment. Adrenal hypertrophy and steroidogenic arrest of the adrenal gland along with altered level of brain monoamines in the midbrain and diencephalons following arsenic intoxication were also ameliorated after hCG coadministration. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:29–41, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20309     

Avian oviduct motility induced by prostaglandin E1

Oviduct segments from infundibulum, magnum, uterus, uterovaginal junction and vagina of actively laying hens at preoviposition time were tested for their contractile reaction to prostaglandin E₁ by or methods. Maximum stimulatory response was observed from the muscular strips of the proximal oviduct segment (infundibulum) and a complete relaxation was recorded from the distal part (vagina) at molar concentrations of 1.4 × 10⁻⁷, 3.4 × 10⁻⁷ and 7.0 × 10⁻⁷. The uterine strips reacted with a stimulatory response at higher concentrations (1.4 × 10⁻⁶ and 2.8 × 10⁻⁶ moles), but lacked any significant change at lower concentrations. The uterovaginal muscular strips showed a mild but prolonged inhibitory response, while the magnum responded with a significant increase in the luminal pressure when tested . It is concluded that PGE₁ exerts a stimulatory effect on the uterus to initiate transport of the egg to subsequent segments (uterovaginal junction and vagina), which relax under PGE₁ influence and allow passage of the egg by pressure differences.     

The preservation of Mullerian inhibiting substance during long-term freezing of testicular fragments

Mullerian Inhibiting Substance, a fetal testicular hormone found in most mammalian species, causes regression in the male of the Mullerian duct, the anlagen of the fallopian tube, uterus, and upper vagina. Limitations to study of this substance in the past have been posed by its short period of production and by its localized and specific action. We have been able to store testicular fragments that continue to demonstrate detectable Mullerian Inhibiting Substance activity for up to 5 months by using techniques of slow freezing which approximate 1 °C/min, cryoprotective additives, storage in liquid nitrogen, and rapid thawing. These fragments then can be pooled for biochemical and endocrinological studies. In addition, unknown fragments can be transported long distances for assay of Mullerian Inhibiting Substance.     

Trace element content in the internal female genitalia of the fetus in the 2d half of pregnancy]

The dynamics of increasing the concentration of microelements in the ovary, uterine tubes, uterus and vagina in the second half of intrauterine life were studied. Changes in the concentration of microelements depend on increasing the weight of the organs in question beginning from the 4th up to the 10th month of the fetal period. Hence, copper, zinc, manganese, titanium, lead, molybdenum are necessary for development and formation of internal female genitalia.     

XY gonadal dysgenesis with female phenotype (author's transpl)]

In this paper, we are dealing with the study of a case of multiple somatic malformations, with external female genitals and 46 XY caryotype. The anatomical and histological study of the genital organs, allows us to verify the existence of internal genital organs; consisting essentially in tubes, bicornous uterus, a gonadal ligament in a normotopical position, Wolffian remains and the absence of a vagina. The external female genitals are completely normal. When we interpreted these findings, we paid special attention to the relation existing between the abnormal presence of the Wolffian remains, male genotype, and typical female genital structures. Taking account of the latest scientific advances concerning genital development, we considered the possibility of the existence of secretions of a "masculinizing" substance from the gonad, before its morphological differentiation, which was interrupted by an etiological undetermined noxa. When this evolution was arrested, together with the secretions of the masculinizing substance, the genital development continued normally for a female. The terminal teratogenic period for this malformation is situated from the 5th to the 6th week of gestation (human embryos from 11 to 14 mm., Streeter Horizon XVII).     

Fine Structure of the Female Genital System in Phytoseiid Mites with Remarks on Egg Nutrimentary Development, Sperm-Access System, Sperm Transfer, and Capacitation (Acari, Gamasida, Phytoseiidae)

The fine structure of the female genital system is described in two phytoseiid species: Phytoseiulus persimilis Athias-Henriot (mating females) and Typhlodromus rhenanoides Athias-Henriot (overwintering females). The female genital tract is composed of an unpaired gonad, the uterus (oviduct I), and the vaginal duct (oviduct II). The latter leads to the vagina (genital atrium), into which a pair of vaginal glands opens. The gonad (ovary s.l.) has two components: the ovary (s.str.) where germ cells develop and the lyrate organ serving as a nutrimentary compartment. In the ovary (s.str.), somacells and germ cells are observed. The germ cells surround a central tissue, to which they have direct contact with a nutritive cord at least in the previtellogenic phase during oogenesis. In fertilized females, cells likely representing capacitated sperm cells are also found in the ovary. The lyrate organ has two arms that extend anteriorly but join in their posterior part in front of the ovary (s.str.). The lyrate organ is composed of a somatic (supporting) and a nutritive tissue. The nutritive tissue, which is a syncytium, is continuous with the central tissue. The uterus starts from the ventral region of the central tissue. Finally, the ultrastructure of the sperm-access system, composed of paired solenostomes, major and minor ducts, emboli, calyces, and vesicles, is reported and functional aspects are discussed. The minor ducts end in the somatic tissue of the ovary s.str. However, because of its extremely reduced lumen and the peculiar morphology of its beginning, it seems unlikely that the minor duct lumen serves as a simple route for the sperm towards the ovary.     

The morphogenetic potentials of endometrial and ovarian tumor cells when cultured on soft agar]

Morphofunctional peculiarities of tumor cells from 15 endometrial adenocarcinomas and 2 ovarian tumors have been investigated at the ultrastructural level. These cells could develop two types of colonies in soft agar: those with histotypical differentiation (numerous microvilli, well developed tight junctions, desmosomes, secretory granules), and those without it (absence of epithelial features, ability of tumor cells to produce filamentous extracellular matrix and striated collagen fibrils which are characteristic of fibroblastic cells). The addition of progesterone and tamoxifen to cell cultures resulted in rising the level of cell differentiation in the colonies. The fact that endometrial and ovarian cancer cells can express the properties specific of connective tissue cells may suggest a multipotention of the Mullerian epithelium derivatives to shed light on the histogenesis of the mixed Mullerian tumors of uterus.     

Ultrasonographic evaluation of the pre-pubertal development of the reproductive tract in beef heifers

To study the development of the reproductive tract in heifers, the ovaries, uterus, cervix and vagina were examined by transrectal ultrasonography every 2 weeks, from 2 to 60 weeks after birth. First ovulation occurred at 63.7 +/- 1.1 weeks of age. Ovarian dimensions increased rapidly from 2 to 14 weeks of age, and increased again after 34 weeks of age (P<0.05). The size of the largest ovarian follicles increased from 8 to 14 weeks of age, from 38 to 42 weeks of age, and finally from 52 to 60 weeks of age (P<0.05). The number of follicles > or =3 mm in diameter tended to increase from 6 to 14 weeks of age (P<0.10) and increased significantly from 6 to 60 weeks of age (P<0.05). Mean numerical pixel values of the ovarian images decreased from 4 to 26 weeks of age, and then rose to 44 weeks of age (P<0.05). Diameter of the uterine body, cervix and vagina increased from 2 to 20-24 weeks of age, and again after 32 weeks of age (P<0.05). Mean numerical pixel values for the uterus and vagina decreased initially (uterus: 4-8 weeks and vagina: 6-22 weeks of age) and then increased (uterus: 14-42 weeks and vagina: 22-32 weeks of age; P<0.05). Pixel heterogeneity showed a consistent peak at 20-22 weeks of age for the uterus, cervix and vagina (P<0.05). In summary, in the heifer calf, the marked growth of the reproductive tract in the first few months of age, and prior to first ovulation, reflects phases of increased ovarian follicle (> or =3 mm in diameter) numbers and size. Ultrasonographic image analysis revealed patterns of numerical pixel values and heterogeneity that may be useful in determining important stages of growth and differentiation of the reproductive system.     

Urogenital vasculature and local steroid concentrations in the uterine branch of the ovarian vein of the female tammar wallaby (Macropus eugenii)

The urogenital vasculature of the tammar comprises 4 major paired arteries and veins: the ovarian, the cranial urogenital, the caudal urogenital and the internal pudendal artery and vein. The ovarian artery and vein and their uterine branches which supply the ovary, oviduct and uterus, ramify extensively. Each anterior urogenital artery and vein supplies the caudal regions of the ipsilateral uterus, lateral and median vagina and cranial parts of the urogenital sinus. The caudal urogenital arteries and veins supply the urogenital sinus and caudal regions of the bladder. The internal pudendal artery and vein vascularize the cloacal region, with some anastomoses with branches of the external pudendal vessels. Anastomoses connect the uterine branch of the ovarian artery with the uterine branch of the cranial urogenital and cranial branches of the caudal urogenital arteries, and connect the caudal urogenital and the internal pudendal arteries. Anastomotic connections between the left and right arterial supply also occur across the midline of the cervical regions of the uteri and the anterior lateral vaginae. Similar connections are seen in the venous system. The uterine branch of the ovarian artery ramifies extensively very close to the ovary, giving a plexiform arrangement with the ovarian veins, and also with the uterine venous system on the lateral side of each uterus. This plexiform structure provides an anatomical arrangement which could allow a local transfer of ovarian hormones from ovarian vein into the uterine arterial supply, and thence to the ipsilateral uterus. Progesterone concentrations in plasma from the mesometrial side of the uterine branch of the ovarian vein are markedly higher than in tail vein plasma, especially during the 'Day 5 peak' early in pregnancy, and also at full term. There is also a marked decrease in progesterone concentration from all sites immediately before birth as previously reported for peripheral plasma. These results support the suggestion of a countercurrent transfer mechanism, at least for progesterone, and possibly other hormones, between the ovarian vein and uterine artery. Such a local transfer could explain the different morphological responses of the endometria of the two adjacent uteri during pregnancy in macropodid marsupial species.