Fetal Brain Damage in Human Fetuses with Congenital Cytomegalovirus Infection: Histological Features and Viral Tropism.

Human cytomegalovirus (HCMV) causes congenital neurological lifelong disabilities. To date, the neuropathogenesis of brain injury related to congenital HCMV (cCMV) infection is poorly understood. This study evaluates the characteristics and pathogenetic mechanisms of encephalic damage in cCMV infection. Ten HCMV-infected human fetuses at 21 weeks of gestation were examined. Specifically, tissues from different brain areas were analyzed by: (i) immunohistochemistry (IHC) to detect HCMV-infected cell distribution, (ii) hematoxylin-eosin staining to evaluate histological damage and (iii) real-time PCR to quantify tissue viral load (HCMV-DNA). The differentiation stage of HCMV-infected neural/neuronal cells was assessed by double IHC to detect simultaneously HCMV-antigens and neural/neuronal markers: nestin (a marker of neural stem/progenitor cells), doublecortin (DCX, marker of cells committed to the neuronal lineage) and neuronal nuclei (NeuN, identifying mature neurons). HCMV-positive cells and viral DNA were found in the brain of 8/10 (80%) fetuses. For these cases, brain damage was classified as mild (n = 4, 50%), moderate (n = 3, 37.5%) and severe (n = 1, 12.5%) based on presence and frequency of pathological findings (necrosis, microglial nodules, microglial activation, astrocytosis, and vascular changes). The highest median HCMV-DNA level was found in the hippocampus (212 copies/5 ng of human DNA [hDNA], range: 10-7,505) as well as the highest mean HCMV-infected cell value (2.9 cells, range: 0-23), followed by that detected in subventricular zone (1.7 cells, range: 0-19). These findings suggested a preferential viral tropism for both neural stem/progenitor cells and neuronal committed cells, residing in these regions, confirmed by the expression of DCX and nestin in 94% and 63.3% of HCMV-positive cells, respectively. NeuN was not found among HCMV-positive cells and was nearly absent in the brain with severe damage, suggesting HCMV does not infect mature neurons and immature neural/neuronal cells do not differentiate into neurons. This could lead to known structural and functional brain defects from cCMV infection.

Ultrastructural and Immunohistochemical Diagnosis of a Neonatal Herpes Simplex Virus Infection Presenting as Fulminant Hepatitis: A Case Report.

TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex Virus and Syphilis) infections are a major cause of intrauterine and perinatal infections with associated morbidity and mortality. Neonatal Herpes Simplex Virus infection caused by an enveloped, double-stranded DNA virus of the Herpesviridae family is devastating and fatal. Herpes Viruses are not hepatotropic but may rarely cause hepatitis. Most cases of HSV hepatitis rapidly progress to fulminant hepatic failure and often fatal before the diagnosis or transplantation. Nowadays, despite the availability of antiviral treatment (acyclovir), the outcome remains poor because of late identification of hepatic Herpes Simplex Virus (HSV) infection. We report a male neonate suspected with a metabolic/mitochondrial disease and multi-organ involvement but who developed a fulminant hepatic failure and disseminated coagulopathy secondary to HSV type 1 (HSV-1) infection. The postmortem diagnosis was performed demonstrating HSV-1 in liver tissue by transmission electron microscopy and by retrospective detection of HSV specific antigens by immunohistochemistry.

Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease.

OBJECTIVE: The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. DESIGN: Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. RESULTS: Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. CONCLUSIONS: Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease.

Gluten-Free Diet and Lipid Profile in Children With Celiac Disease: Comparison With General Population Standards.

OBJECTIVES: A gluten-free diet (GFD) may carry high energy and fat load. We verified lipid profile and dietary indicators cross-sectionally and prospectively in patients with celiac disease (CD). METHODS: In any consecutive child receiving a GFD (group 1) or newly diagnosed as having CD (group 2), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), anthropometric data, physical activity, and a 24-hour food diary were collected during follow-up visits (yearly in group 1 and during the first year of GFD in group 2). RESULTS: In group 1 (132 girls, 73 boys, 10.7 ±â€Š4.2 years), TC (P = 0.006), TG (P = 0.014), and HDL (P = 0.019) were significantly higher in girls than in boys. Compared with the general pediatric population, group 1 girls had higher TC, TG, HDL, and low-density lipoprotein; group 1 boys had lower TC, TG, and low-density lipoprotein and higher HDL. TC was significantly and positively affected by age, sex, and time receiving GFD, whereas HDL was significantly and positively affected by body mass index, diastolic BP, and sex; TG was negatively affected by diastolic BP. Compared with recommendations, group 1 children introduced less calories, iron, and calcium; one-third more sodium; similar amounts of fiber; and twice as many proteins. In group 2 (20 girls, 10 boys, 8.6 ±â€Š3.55 years), TC did not change over time and TG diminished, whereas HDL, blood glucose, and body mass index increased; saturated fats and caloric intake were below recommendations, whereas proteins were excessively introduced. Fibers were optimal. HDL was inversely correlated to calories and saturated fat (R²â€Š= 80, P = 0.011). CONCLUSIONS: Lipid profiles of children with CD differ across sexes and from reference population. GFD, being unexpectedly appropriate in fibers and fat proportion, may be a contributor.

Appendiceal neuroendocrine tumours in childhood: Italian TREP project.

BACKGROUND: Neuroendocrine tumours (NETs) of the appendix are slow-growing tumours and, although rare, they are the most common gastrointestinal epithelial tumours in childhood and adolescence. The treatment and the follow-up screenings have not been standardised. In addition to this, although tumour size is considered the main prognostic variable to define the aggressiveness of approach, a precise cutoff needs to be established. METHODS: A total of 113 patients younger than 18 years with a diagnosis of appendiceal NETs were registered as of January 1, 2000, until May 30, 2013, within the Rare Tumors in Pediatric Age (TREP) project, an Italian multi-institutional network dedicated to rare tumours in children and adolescents. The recommendations of the Rare Tumors in Pediatric Age study included imaging and laboratory investigations. The treatment after appendectomy was decided on the basis of histology, tumour size, and imaging; primary reexcision (PRE) was not recommended in completely excised tumours, regardless of tumour size and invasiveness. RESULTS: A total of 113 of 113 patients had a diagnosis of well-differentiated NETs; in 108 of 113 the tumour was smaller than 2 cm and in 5, larger than 2 cm. Excision margins were free in 111 of 113 patients. In 3 of 113 a PRE was performed, and in 1 residual tumour was detected. All 113 of 113 patients are alive in complete remission (median follow-up of 41 months). CONCLUSIONS: Reported data and our experience showed that no relapse or death occurred in children and adolescents affected by appendiceal NETs. Appendectomy alone should be considered curative for most patients, and a more aggressive surgical approach is warranted in the cases with incompletely excised tumours.

Fatal Deterioration of a Respiratory Syncytial Virus Infection in an Infant with Abnormal Muscularization of Intra-Acinar Pulmonary Arteries: Autopsy and Histological Findings.

Respiratory syncytial virus (RSV) infection represents a global and noteworthy cause of hospitalization and death in infants of less than 1 year of age. The typical clinical manifestation is bronchiolitis, an inflammatory process of the small airways. The symptoms are usually a brief period of low-grade fever, cough, coryza, breathing difficulties, and reduced feeding. The progression of the disease is difficult to predict, even in previous healthy subjects. Symptoms may also be subtle and underestimated, thus leading to sudden unexpected infant death (SUID). In these cases, RSV infection is discovered at autopsy, either histologically or through real-time reverse transcription polymerase chain reaction (RT-PCR) performed on nasopharyngeal swabs. Herein, we describe a case of RSV infection in a 6-month-old infant with no risk factors, who rapidly deteriorated and unexpectedly died of respiratory insufficiency in a hospital setting. RT-PCR on nasopharyngeal swabs revealed RSV. The autopsy showed diffuse lymphogranulocytic bronchitis and bronchiolitis, and multiple foci of acute pneumonia. Abnormal muscularization of the intra-acinar pulmonary arteries was also observed, which likely contributed to worsening the lung impairment.

The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization.

We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1alpha and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of alpha-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1alpha stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1alpha stabilization.

Gestational and fetal outcomes in B19 maternal infection: a problem of diagnosis.

Parvovirus B19 infection during pregnancy is a potential hazard to the fetus because of the virus' ability to infect fetal erythroid precursor cells and fetal tissues. Fetal complications range from transitory fetal anemia and nonimmune fetal hydrops to miscarriage and intrauterine fetal death. In the present study, 72 pregnancies complicated by parvovirus B19 infection were followed up: fetal and neonatal specimens were investigated by serological and/or virological assays to detect fetal/congenital infection, and fetuses and neonates were clinically evaluated to monitor pregnancy outcomes following maternal infection. Analysis of serological and virological maternal B19 markers of infection demonstrated that neither B19 IgM nor B19 DNA detected all maternal infections. IgM serology correctly diagnosed 94.1% of the B19 infections, while DNA testing correctly diagnosed 96.3%. The maximum sensitivity was achieved with the combined detection of both parameters. B19 vertical transmission was observed in 39% of the pregnancies, with an overall 10.2% rate of fetal deaths. The highest rates of congenital infections and B19-related fatal outcomes were observed when maternal infections occurred by the gestational week 20. B19 fetal hydrops occurred in 11.9% of the fetuses, and 28.6% resolved the hydrops with a normal neurodevelopment outcome at 1- to 5-year follow-up. In conclusion, maternal screening based on the concurrent analysis of B19 IgM and DNA should be encouraged to reliably diagnose maternal B19 infection and correctly manage pregnancies at risk.

Fetal Presentation of Mediastinal Immature Teratoma: Ultrasound, Autopsy and Cytogenetic Findings.

Teratomas are the most common congenital tumors, occurring along the midline or paraxial sites, or uncommonly, the mediastinum. Teratomas are classified as mature, containing only differentiated tissues from the three germinal layers; and immature, which also present with neuroectodermal elements, ependymal rosettes, and immature mesenchyme. Herein, we describe a new case of fetal mediastinal immature teratoma detected at 21 weeks of gestational age (wga) + 1 day with thorough cytogenetic analysis. Ultrasound (US) showed a solid and cystic mass located in the anterior mediastinum, measuring 1.8 × 1.3 cm with no signs of hydrops. At 22 wga, US showed a mass of 2.4 cm in diameter and moderate pericardial effusions. Although the prenatal risks and available therapeutic strategies were explained to the parents, they opted for termination of pregnancy. Histology showed an immature teratoma, Norris grade 2. Karyotype on the fetus and tumor exhibited a chromosomal asset of 46,XX. The fetal outcome in the case of mediastinal teratoma relies on the development of hydrops due to mass compression of vessels and heart failure. Prenatal US diagnosis and close fetal monitoring are paramount in planning adequate treatment, such as in utero surgery, ex utero intrapartum therapy (EXIT) procedure, and surgical excision after birth.

Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review.

Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps. Despite both displayed striking clinical (and, in the first case, familial) manifestations of Cowden Syndrome (PTEN Hamartoma Tumor Syndrome-PHTS), they had not been recognized before. Diagnosis of PHTS was confirmed by the detection of causative PTEN variants. Pathological examination of the polyps showed multiple histology types: hyperplastic, juvenile, serrated and lymphoid. Hyperplastic polyps analyzed from both patients failed to show BRAF V600E and KRAS codon 12/13 mutations, which provides evidence against their potential to evolve to colorectal cancer through the serrated pathway. We then reviewed the literature on gastrointestinal polyps detected in patients with Cowden Syndrome, in order to provide a comprehensive scenario of presentations: among a total of 568 patients reported in the literature, 91.7 % presented with colon polyps, with 63.0 % having two or more different histological types of polyps; besides, 58.5 % had extra-colonic polyps (located either in stomach and/or in small intestine). Finding multiple polyps with mixed and/or unusual histology should alert gastroenterologists and pathologists about the possible diagnosis of Cowden Syndrome and prompt the search for other manifestations of this condition in the patient.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome.

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

Autochthonous Cases of Mucosal Leishmaniasis in Northeastern Italy: Clinical Management and Novel Treatment Approaches.

Mucosal leishmaniasis (ML) is a rare clinical variant of tegumentary leishmaniasis in Mediterranean Europe. Here we report on three autochthonous cases of head and neck ML in patients living in Northeastern Italy. Patients presented with non-specific, long-standing symptoms of upper respiratory tract involvement, mimicking other diseases. Parasitological diagnosis was reached by histopathology, immunohistochemistry and molecular biology on tissue specimens. Leishmania infantum was identified by molecular typing in all three cases. All patients reached a complete remission with protracted multivalent antileishmanial drugs; in one case, a novel approach of combined medical and endoscopic surgical treatment was carried out. High clinical suspicion led to a prompt diagnosis and deployment of a multivalent treatment. ML should be considered in the differential diagnosis of nasal, oral, and pharyngolaryngeal lesions in endemic areas. A prompt diagnosis is mandatory to establish a correct management; different antileishmanial medications as well as endoscopic surgical options may be required to reach a complete remission.

Diffuse primary cutaneous infection by Alternaria alternata in a liver transplant recipient with pulmonary nocardiosis: Importance of prompt identification for clinical resolution.

Fungal infections are rare in the general population but are an emerging cause of disease in immunosuppressed patients, especially solid organ transplant recipients. Here, we report the case of a female Caucasian liver transplant patient who developed pulmonary nocardiosis two months after an episode of liver rejection. At the time of lung nocardiosis, she was being treated with tacrolimus and corticosteroids and suffered from diffuse papular skin lesions. She was initially suspected of having a cutaneous nocardial infection but culture examination revealed the presence of a dematiaceous fungus; Alternaria alternata. The prompt identification of the fungus and administration of oral Voriconazole resolved the skin infection with complete remission.

The variegated histopathological features of atypical lentiginous melanocytic nevi: a single institution experience.

BACKGROUND: Atypical lentiginous melanocytic nevi (ALMNs) are atypical pigmented lesions with histopathological features similar to those of dysplastic nevi, with a lentiginous pattern. Variable histopathological features of ALMNs were observed in our practice. METHODS: We described the histopathological features of ALMNs diagnosed in the period 2009-2015. Our cases were divided into 2 groups: Group 1: ALMNs showing the same histopathological features as previously described in the literature; Group 2: ALMNs with different features. RESULTS: Twenty-nine ALMNs were diagnosed; 2 groups of ALMNs were identified. Group 1 ALMNs showed a constant, mild epidermal acanthosis; frequently, an inflammatory infiltrate and dermal fibrosis, cytological atypia and mild architectural atypia. Group 2 ALMNs showed a constant psoriasis-like acanthosis with a hypercellularity of the rete ridges; cytological atypia was rare, whereas architectural atypia was constantly observed. Immunohistochemistry (MART-1 staining) revealed that the melanocytes were localized at the dermo-epidermal junction in both groups. ALMNs showed a broad spectrum of histopathological features. CONCLUSIONS: Our main finding was a constant architectural atypia in all lesions of Group 2. The identification of a unique type of ALMN seems no longer possible. The correct recognition of such benign, though atypical, melanocytic lesions is important in order to avoid an overdiagnosis of cutaneous melanoma and to prevent their potential evolution to the latter.

Pathophysiology of Hyperechogenic Bowel in Congenitally Human Cytomegalovirus Infected Fetuses.

Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach's myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB.

An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells.

A disruptive frameshift mtDNA mutation affecting the ND5 subunit of complex I is present in homoplasmy in a nasopharyngeal oncocytic tumor and inherited as a heteroplasmic germline mutation recurring in two of the patient's siblings. Homoplasmic ND5 mutation in the tumor correlates with lack of the ND6 subunit, suggesting complex I disassembly. A few oncocytic areas, expressing ND6 and heteroplasmic for the ND5 mutation, harbor a de novo homoplasmic ND1 mutation. Since shift to homoplasmy of ND1 and ND5 mutations occurs exclusively in tumor cells, we conclude that complex I mutations may have a selective advantage and accompany oncocytic transformation.

Does stent placement for advanced colon cancer increase the risk of perforation during bevacizumab-based therapy?

BACKGROUND & AIMS: Data on the safety of bevacizumab-based therapies for patients carrying a self-expandable metallic stent (SEMS) for occlusive colon cancer are lacking. We report 2 cases of colon perforation observed in our case series of patients with SEMS for occlusive colon cancer. METHODS: Patients with occlusive symptoms caused by colon cancer received a colonic stent under endoscopic and radiologic guidance. RESULTS: Over a 10-month period, 28 patients with occlusive colon cancer were treated with stent placement. The stent was placed as a bridge to surgery in 12 patients who were treated surgically within 4 to 78 days after the endoscopic procedures, without any stent-related complications. Seven patients did not receive any other antitumor treatment as a result of concomitant comorbidities. Nine patients with both primary tumor and metastatic lesions were treated with medical therapy. Over a median follow-up period of 131 days colonic perforation occurred in the 2 patients treated with a combination of capecitabine and oxaliplatin plus bevacizumab. CONCLUSIONS: Further studies are needed to clarify whether SEMS placement increases the risk of perforation caused by bevacizumab-based therapies.

Placental endothelial cells can be productively infected by Parvovirus B19.

BACKGROUND: Parvovirus B19 vertical transmission occurs in about 30% of cases of maternal infection and may result in foetal hydrops or intrauterine foetal death. Details on the mechanism of transplacental transmission of B19 virus and subsequent foetal infection have not been elucidated. OBJECTIVE: To investigate the extent and distribution of B19 virus infection in placental tissues. STUDY DESIGN: Virological, histological, electron microscopy, immunohistochemical and immunofluorescence analysis of placental tissues obtained from a case of intrauterine foetal death caused by B19 virus. RESULTS: Real-time PCR analysis showed B19 virus DNA in placental samples. Histology, immunohistochemistry and electron microscopy demonstrated the concomitant infection of both foetal erythroid precursors and placental endothelial cells. In situ hybridisation for B19 virus nucleic acids, immunohistochemistry for B19 virus proteins and double labelling immunofluorescence confirmed that endothelial cells were productively infected by B19 virus. CONCLUSION: Foetal capillary endothelium in placental villi can be an additional target of productive B19 virus infection. Infection of placental endothelial cells may lead to a structural and functional damage critical both for altering maternal-foetal blood exchanges and for spreading the infection to the foetus, possibly concurring to the development of foetal hydrops and intrauterine foetal death.

Effect of long-term testosterone administration on the endometrium of female-to-male (FtM) transsexuals.

INTRODUCTION: Long term safety of testosterone (T) administration in women is still unknown. In particular few and discordant data exists on the effects of T on the endometrium. AIM: The aim of this study was to investigate the effects of long-term T treatment on endometrium histology and proliferation in female to male transsexual subjects (FtM). We compared these endometria with those of young women in the proliferative phase (PM) of the cycle and with those of post menopausal women (M). METHOD: Endometrial samples from 27 FtM treated with T (intramuscular injection of 100 mg Testoviron Depot /10 days for at least one year), 30 M undergoing vaginal hysterectomy, and 13 PM undergoing hysteroscopy for infertility problems were collected. Endometrial proliferation was evaluated on the basis of histopathology and expression of the proliferation marker Ki-67. Both M and PM women had not received any hormonal treatment for at least one year. MAIN OUTCOME MEASURE: Circulating total testosterone (TT), estradiol (E), progesterone (P), insulin and glucose levels were measured in FtM and PM subjects. RESULTS: FtM had received T for 33.6 +/- 21.3 months (mean +/- SD). In FtM subjects, histological analysis found inactive endometrium similar to the atrophic menopausal endometrium. The expression of Ki-67 in the glands, stroma and glands and stroma together was significantly (p < 0.0005) lower in FtM than in PM women and was similar in the FtM and M groups. Small polyps were detected in 5 of the 27 FtM subjects. CONCLUSIONS: In conclusion our data suggest that exogenous T administration does not stimulate endometrial proliferation in FtM transsexuals and indeed may have atrophic effects.