Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease.

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7-/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7-/- background (Emv2-/-Tlr7-/-) and found that Emv2-/-Tlr7-/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1-/-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.

An Enteropathy-like Indolent NK-Cell Proliferation Presenting in the Female Genital Tract.

Natural killer (NK) cell enteropathy is a lymphoproliferative disorder, initially described by Mansoor and colleagues, that presents in the gastrointestinal tract, and is often mistaken for extranodal NK/T-cell lymphoma on first assessment. This population of cells in this process have an NK-cell phenotype (CD3, CD56, CD2, CD7), lacks evidence of Epstein-Barr virus infection, has germline rearrangement of the T-cell receptor, and a very indolent clinical course. Indeed, many of such patients had been originally diagnosed as having an NK/T-cell lymphoma, and subsequently received chemotherapy. We report a unique case where an indolent lymphoproliferative disorder with features that resemble NK-cell enteropathy is encountered for the first time outside the gastrointestinal tract, specifically in the female genitourinary tract. We provide morphologic, immunophenotypic, and molecular documentation of such, in association with a completely indolent clinical behavior of this type of process.

Functional Expression of FSH Receptor in Endometriotic Lesions.

CONTEXT: FSH receptor (FSHR), besides being expressed in gonads, is also expressed in some extragonadal tissues at low levels. OBJECTIVE: We examined the functional expression of FSHR in different types of endometriotic lesions. DESIGN: Extensive studies were carried out to detect functional FSHR expression and FSH-stimulated estrogen production in ovarian endometriomas and recto-vaginal endometriotic nodules (RVEN). Normal endometrium, ovary, and myometrium tissues from nonpregnant cycling women served as controls. SETTINGS: This laboratory-based study was carried out on tissue specimens from patients with endometriosis and healthy donors. RESULTS: Endometriotic lesions and normal secretory-phase endometrium showed FSHR expression at both mRNA and protein level. RVEN and ovarian endometrioma demonstrated up-regulated CYP19A1, dependent on the activation of CYP19A1 proximal promoter II. Estrogen receptor-ß (ESR2) expression was significantly increased in RVEN vs normal endometrium. Recombinant human FSH stimulation of RVEN explants significantly increased estradiol production and CYP19A1 and ESR2 expression. FSHR was up-regulated in recombinant human FSH-stimulated endometrial and decidualized stromal cells with increased CYP19A1 expression. CONCLUSIONS: We described a novel functional FSHR expression, where FSH-stimulated CYP19A1 expression and estrogen production in RVEN are demonstrated. This locally FSH-induced estrogen production may contribute to the pathology, development, progression, and severity of RVEN.

A rare familial case of endometriosis with very severe gynecological and obstetric complications: novel genetic variants at a glance.

Endometriosis is influenced by both genetic and environmental factors. Genetic factors make up about half of the variation in endometriosis. Nevertheless, the genetics of endometriosis remains complex and in part unsolved, but recently, based on the results of few genome-wide association studies, some genetic susceptibility loci have been identified as associated robustly with the disease, providing new insights into potential pathways leading to endometriosis. Here, we present the case of a familial cluster composed by 3 sisters and their mother, all affected by endometriosis. Very severe gynecological and obstetric complications caused by the invasiveness of the disease have been observed in all members of the single family. The entire family has been genotyped for 3 single-nucleotide polymorphisms identified as associated with endometriosis. All the family members were homozygotes for the risk allele G for the rs1333049 variant in the CDKN2BAS locus. The genotype-phenotype association is just at the beginning of endometriosis research promising to face novel concepts for disease diagnosis and treatment.

Hymenal anomalies in twins--review of the literature and case report.

UNLABELLED: Subocclusive hymenal variants, such as microperforate or septate hymen, impair somatic functions (e.g., vaginal intercourse or menstrual hygiene) and can negatively impact the quality of life of young women. We know little about the prevalence and inheritance of subocclusive hymenal variants. So far, eight cases of familial occurrence of occlusive hymenal anomalies (imperforate hymen) have been reported. In one of these cases, monozygotic twins were affected. We are reporting the first case of subocclusive hymenal variants (microperforate hymen and septate hymen) in 16-year-old white dizygotic twins. In addition, we review and discuss the current evidence. CONCLUSION: The mode of inheritance of hymenal variants has not been determined so far. Because surgical corrections of hymenal variants should be carried out in asymptomatic patients (before menarche), gynecologists and pediatricians should keep in mind that familial occurrences may occur.

Symptoms at postmenopause: genetic and psychosocial factors.

OBJECTIVE: Menopause symptoms result from the interaction of estrogen deprivation, psychosocial influences, and genetic factors. We examined the influence of stress and of estrogen receptor-α (ER-α; PvuII and XbaI) and serotonin transporter (5-HTT) polymorphisms on symptoms at postmenopause. METHODS: We studied 290 urban women from three cities in Mexico. General characteristics, menopause symptoms, and scores of perceived stress, effort-reward imbalance, dominance, and submission were collected. A fasting blood sample was obtained for hormone measurements and genotypification. RESULTS: Women had a mean ± SD age of 54.4 ± 4.5 years and BMI of 29.5 ± 4.9 kg/m. The frequency of hot flashes was 75.5%; vaginal dryness, 57.8%; and diminished sexual interest, 78.7%. Follicle-stimulating hormone and estradiol levels were 59 ± 27 mIU/mL and 22 ± 29 pg/mL, respectively. Women from Torreón had higher schooling and less parity but higher scores for depression and lower submission. Hot flashes were more frequent in women from León. Genotype distribution was similar among cities. Lower scores for dominance were found in women with the pp and xx ER-α genotypes. Increased smoking habit was found for the SS genotype of 5-HTT. Factors significantly associated with symptoms were years since menopause, with hot flashes (negative), and with diminished sexual interest (positive); dominance was negatively associated with depression, perceived stress, and vaginal dryness; submission was positively associated with depression, perceived stress, anxiety, and hot flashes; and effort-reward imbalance was positively associated with anxiety, hot flashes, and perceived stress. CONCLUSIONS: Symptoms at postmenopause were associated mainly with dominance, submission, and effort-reward imbalance. The pp genotype of ER-α showed lower scores of dominance.

Altered gene expression profile in vaginal polypoid endometriosis resembles peritoneal endometriosis and is consistent with increased local estrogen production.

BACKGROUND: In a university hospital setting, a 25-year-old woman presented with large vaginal and cervical polyps. Past medical history was significant for stage IV endometriosis. Polypectomy was performed and the polyps were histologically consistent with endometriosis. Gene expression was compared with control vaginal tissue to assess if the altered gene expression profile was similar to peritoneal endometriosis. METHODS AND RESULTS: Using quantitative reverse transcription, real-time PCR, estrogen receptor-ß expression was found to be upregulated 10-fold while estrogen receptor-α expression was downregulated 5-fold in the vaginal polyp relative to control vaginal tissue. The estrogen-synthesizing enzyme aromatase was upregulated 8-fold and 3ß-hydroxysteroid dehydrogenase was upregulated 400-fold in the polyp. Immunohistochemical staining revealed altered cell type localization for progesterone receptor in the polyp and increased cell proliferation in polyp stromal cells relative to control. CONCLUSIONS: Increased proliferation in the vaginal polypoid endometriotic tissue may be due to increased local estrogen production. The altered gene expression profile was very similar to the altered gene expression profile seen in peritoneal endometriosis.

High incidence of distal vaginal atresia in mice lacking Tyro3 RTK subfamily.

Vaginal atresia is a congenital abnormality of the female genitourinary system, and the specific molecular mechanism leading to failure of vaginal development remains to be elucidated. Here, we report that the female mice lacking Tyro3 RTK subfamily (Tyro3, Axl, and Mer) exhibit a high incidence of distal vaginal atresia. The ratios of the vaginal atresia in Tyro3 RTKs mutant female mice are as follows: 2.5% for Mer(-/-) mice, 4.0% for Axl(-/-)Mer(-/-), 3.7% for Mer(-/-)Tyro3(-/-), 16.06% for Tyro(-/-)Axl(-/-)Mer(-/-) mice. We did not find the vaginal atresia in Axl(-/-), Tyro3(-/-), Axl(-/-) Tyro(-/-), and wild-type mice. These observations suggest that Tyro3 RTKs play roles collaboratively in vaginal development, and Mer is more critical, Axl and Tyro3 support the function of Mer. The phenotype of mice with the vaginal atresia was characterized in this study. Tyro3 RTKs mutant mouse could be a useful model to study the mechanism of vaginal atresia formation.

Pelvic organ prolapse in fibulin-5 knockout mice: pregnancy-induced changes in elastic fiber homeostasis in mouse vagina.

Pelvic organ prolapse is strongly associated with a history of vaginal delivery. The mechanisms by which pregnancy and parturition lead to failure of pelvic organ support, however, are not known. Recently, it was reported that mice with null mutations in lysyl oxidase-like 1 (LOXL1) develop pelvic organ prolapse. Elastin is a substrate for lysyl oxidase (LOX) and LOXL1, and LOXL1 interacts with fibulin-5 (FBLN5). Therefore, to clarify the potential role of elastic fiber assembly in the pathogenesis of pelvic organ prolapse, pelvic organ support was characterized in Fbln5-/- mice, and changes in elastic fiber homeostasis in the mouse vagina during pregnancy and parturition were determined. Pelvic organ prolapse in Fbln5-/- mice was remarkably similar to that in primates. The temporal relationship between LOX mRNA and protein, processing of LOXL1 protein, FBLN5 and tropoelastin protein, and desmosine content in the vagina suggest that a burst of elastic fiber assembly and cross linking occurs in the vaginal wall postpartum. Together with the phenotype of Fbln5-/- mice, the results suggest that synthesis and assembly of elastic fibers are crucial for recovery of pelvic organ support after vaginal delivery and that disordered elastic fiber homeostasis is a primary event in the pathogenesis of pelvic organ prolapse in mice.

Secretory leukocyte protease inhibitor levels in cervicovaginal secretion of elderly women.

OBJECTIVE: Secretory leukocyte protease inhibitor (SLPI) is a potent inhibitor of human leukocyte elastase. The aim of the present study was to examine whether there is an association between the SLPI concentration in the cervicovaginal secretion (CS) and vaginal complaints of post-menopausal women. METHODS: Uterine cervix tissues and CS of peri- or post-menopausal women were obtained. SLPI was assayed by ELISA. To determine the level of SLPI mRNA and the localization of SLPI protein in the uterine cervix, we performed RT-PCR and immunochemical staining, respectively. RESULTS: The levels of SLPI in the CS of post-menopausal women with vaginal complaints were significantly lower that those of post-menopausal women without vaginal complaints. The levels of SLPI in the CS of post-menopausal women were lower that those of peri-menopausal women and post-menopausal women treated with hormone replacement therapy. Positive staining was observed in epithelial cells of the cervix of elderly women, however, the intensity was weaker than that in peri-menopausal women. Positive staining was also observed in gland cells of the cervix of peri-menopausal women, but not in those of post-menopausal women. SLPI transcripts were detected in the cervix of post-menopausal women. The treatment of post-menopausal women with vaginal estrogen increased the concentrations of SLPI in CS of post-menopausal women. CONCLUSIONS: The present findings suggest that the decreased amount of SLPI in the CS of post-menopausal women might be one of the causes of the symptoms of post-menopausal women and contribute to the immunodefense mechanisms of the elderly women.

Vaginal involvement in a woman with Darier's disease: a case report.

BACKGROUND: Involvement of the female genital tract by Darier's disease, an unusual genodermatosis, is uncommon, and the manifestation of the disease in a cervicovaginal smear is exceptionally rare. CASE: A 39-year-old woman had an abnormal Pap smear caused by involvement of the female genital tract by Darier's disease. Cytologic examination showed features consistent with a low grade squamous intraepithelial lesion, but during a biopsy it was found to be vaginal involvement by Darier's disease. CONCLUSION: The correct interpretation of cytologic findings is not possible when the diagnosis of Darier's disease is not known since a low grade squamous intraepithelial lesion cannot be ruled out. This case underlines the importance of knowing the patient's medical histoiy in any moment of medical attention.

Vaginal symptoms in Japanese postmenopausal women: comparison with other climacteric symptoms.

OBJECTIVES: This study was designed to investigate the current status of vaginal symptoms in Japanese postmenopausal women, and to clarify the significance of vaginal symptoms by analyzing their relationship to other climacteric symptoms. METHODS: The complaints of 613 women attending a menopause clinic (mean age +/- standard deviation 53.5 +/- 7.2 years; time since menopause or bilateral oophorectomy 6.4 +/- 6.5 years) were evaluated according to the Keio modified menopause index. RESULTS: In total, 56.4% of subjects had at least one vaginal symptom. The most frequent vaginal symptom was dyspareunia, followed by vaginal dryness, discharge and itching, and the mean prevalence of the four symptoms was 31.7%. The peak intensity of vaginal symptoms occurred in the sixth decade, or 3-5 years after menopause or oophorectomy. Vaginal symptoms were usually associated with other climacteric symptoms, but some occurred independently. CONCLUSIONS: A moderate proportion of Japanese postmenopausal women experience vaginal symptoms, which can occur independently of other climacteric symptoms. Vaginal symptoms therefore warrant careful attention during the treatment of postmenopausal women.

Dominant transmission of imperforate hymen.

OBJECTIVE: Imperforate hymen is an uncommon anomaly of the reproductive tract, occurring in approximately 0.1% of newborn females. The familial occurrence of imperforate hymen in a child, her mother, and her mother's monozygotic twin is reported. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): Three affected family members. MAIN OUTCOME MEASURE(S): Karyotype and pedigree analysis. RESULT(S): The proband, presenting with peritonitis, was evaluated at age 12 for imperforate hymen because this condition was diagnosed in her mother at age 14. At age 14, the mother's monozygotic twin was asymptomatic except for primary amenorrhea and was also demonstrated to have imperforate hymen. No other reproductive system abnormalities were known to be present in the remaining family members. Chromosomal structural analysis confirmed that the mother of the proband had no chromosomal abnormalities. CONCLUSION(S): The occurrence of imperforate hymen in two consecutive generations of a family is consistent with a dominant mode of transmission, either sex-linked or autosomal. Previously reported examples of siblings with imperforate hymen suggested a recessive mode of inheritance. Taken together, these cases suggest that imperforate hymen can be caused by mutations in several genes. This case highlights the importance of evaluating all family members of affected patients. Familial examples of other developmental anomalies of the female reproductive tract also suggest a multifactorial genetic etiology.

Primary non-Hodgkin's lymphoma and malakoplakia of the vagina: a case report.

The vagina is a rare site for both primary non-Hodgkin's lymphoma and malakoplakia. We report a case of concurrent diffuse large B-cell lymphoma and malakoplakia of the vagina in a 67-year-old woman presenting with a vaginal discharge and a vaginal mass. The patient had two biopsy specimens reported as showing malakoplakia only, followed by a third biopsy specimen 10 months later which was diagnosed as diffuse large B-cell lymphoma. Review of the first two biopsy specimens showed areas of histiocytes with Michaelis-Gutman bodies merging with areas of cells with slightly larger nuclei and more amphophilic cytoplasm. Immunohistochemistry for the B-cell marker L-26 (CD20) and polymerase chain reaction analysis of the immunoglobulin heavy chain gene were helpful in retrospectively distinguishing the population of diffuse large B-cell lymphoma from the areas of malakoplakia. The third biopsy specimen showed sheets of large atypical lymphoid cells characteristic of a large cell lymphoma. Malakoplakia has been described in association with a variety of cancers, and this is only the second report of malakoplakia associated with non-Hodgkin's lymphoma. Considering the rarity of these two entities in the vagina, it is unlikely that the association in this case is coincidental, raising the possibilities of an unusual reaction to the presence of lymphoma or a common pathogenesis such as underlying chronic inflammation. Epstein-Barr virus DNA was detected in the second biopsy specimen, suggesting a possible role in the pathogenesis of this lymphoma.

Genetic and physical mapping of the McKusick-Kaufman syndrome.

McKusick-Kaufman syndrome is a human developmental anomaly syndrome comprising mesoaxial or postaxial polydactyly, congenital heart disease and hydrometrocolpos. This syndrome is diagnosed most frequently in the Old Order Amish population and is inherited in an autosomal recessive pattern with reduced penetrance and variable expressivity. Homozygosity mapping and linkage analyses were conducted using two pedigrees derived from a larger pedigree published in 1978. The PedHunter software query system was used on the Amish Genealogy Database to correct the previous pedigree, derive a minimal pedigree connecting those affected sibships that are in the database and determine the most recent common ancestors of the affected persons. Whole genome short tandem repeat polymorphism (STRP) screening showed homozygosity in 20p12, between D20S162 and D20S894 , an area that includes the Alagille syndrome critical region. The peak two-point LOD score was 3.33, and the peak three-point LOD score was 5.21. The physical map of this region has been defined, and additional polymorphic markers have been isolated. The region includes several genes and expressed sequence tags (ESTs), including the jagged1 gene that recently has been shown to be haploinsufficient in the Alagille syndrome. Sequencing of jagged1 in two unrelated individuals affected with McKusick-Kaufman syndrome has not revealed any disease-causing mutations.