SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration.

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFß family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer.

SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-ß (TGF ß) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.

A Novel Ultrasound-Guided Technique for Hysteroscopic Adhesiolysis in High-Risk Patients.

Hysteroscopy is a common gynecologic surgical procedure. Certain diagnoses, notably intrauterine adhesions and cervical stenosis, make hysteroscopy more complicated because of an increased likelihood of complications. Three patients, 1 with cervical stenosis and 2 with Asherman syndrome, underwent ultrasound (US)-guided adhesiolysis. Access to the uterine cavity was obtained by either direct balloon-aided dilation or the US-guided Seldinger technique, followed by balloon-aided dilation to enter the endometrial cavity and disrupt intrauterine/intracervical adhesions. In this case series, we describe a novel approach of using US-guided balloon dilation to safely and effectively treat intrauterine adhesions and to decrease the risk of perforation.

Antimullerian hormone levels are inversely associated with body mass index (BMI) in women with polycystic ovary syndrome.

PURPOSE: The purpose of this paper is to determine whether antimullerian hormone (AMH) levels were associated with BMI in patients with diagnosed infertility, and more specifically, in patients with polycystic ovarian syndrome (PCOS). METHODS: A retrospective cohort study reviewed all females who presented to the clinical investigators' practice between November 2011 and March 2013. The following data was retrieved from the medical record: (1) AMH level, (2) age, (3) BMI, (4) ethnicity, and (5) if infertile, etiology of infertility. RESULTS: AMH levels were available for 489 women. Of these, 104 were diagnosed with PCOS. Overall, there was no association between BMI and AMH (r -0.04, p > 0.05). On the other hand, in the women with PCOS, there was a significant association between BMI and AMH (r -0.31, p < 0.01). CONCLUSIONS: BMI was not associated with AMH levels in the general population of infertile women or in patients without PCOS. However, BMI appeared to be significantly and inversely correlated with AMH in women with PCOS.

Rhabdomyosarcoma of the cervix in adult women and younger patients.

OBJECTIVES: Cervical rhabdomyosarcoma is extremely rare, and there is a paucity of literature on the subject. The purpose of this study was to describe the clinical and pathologic features of cervical rhabdomyosarcoma. METHODS: We retrospectively reviewed all patients with cervical rhabdomyosarcoma who presented to our institution from 1980 to 2010. We reviewed pathologic, demographic, and clinical information. RESULTS: During the study period, 11 females presented with cervical rhabdomyosarcoma. The median age at presentation was 18.4 years, and 6 patients were <19 years old at diagnosis. Vaginal bleeding was the most common presenting symptom, and a vaginal mass was often a co-presenting symptom. Eight patients (73%) presented with stage IB disease, and 8 (73%) presented with the embryonal (botryoid) histologic subtype. Nine patients (82%) received multimodal therapy consisting of surgery with chemotherapy, radiation therapy, or both. All patients were without evidence of disease after completion of primary therapy, but 3 patients experienced local recurrence. At a median follow-up of 23 months, 6 patients (55%) were without evidence of disease, 1 (9%) was alive with disease, 1 (9%) had died of disease, and 3 (27%) had died of other causes. Three patients (27%) had other primary malignancies in addition to rhabdomyosarcoma-1 had a Sertoli-Leydig tumor, 1 had a Sertoli-Leydig tumor and a pinealoblastoma, and 1 had thyroid cancer and a parotid adenocarcinoma. CONCLUSIONS: With multimodal therapy, cervical rhabdomyosarcoma appears to be associated with a good prognosis. Favorable prognostic factors such as early stage at diagnosis and a favorable histologic subtype may contribute to the excellent observed survival.

Unverifiable accomplishments and publications on applications for gynecologic oncology fellowships.

OBJECTIVE: Selection of physicians for fellowships in obstetrics and gynecology subspecialties has become increasingly competitive. The number and quality of research publications is an important factor in the selection process. We sought to estimate the incidence of unverifiable publications among gynecologic oncology fellowship applicants. METHODS: We reviewed the applications to a single gynecologic oncology fellowship program during 2004-2008. Articles and book chapters reported as published, in press, submitted, or in progress were searched for systematically by three reviewers using PubMed and Google. χ2 analysis was used to evaluate associations between demographic factors and unverifiable publications. RESULTS: Two hundred forty-three applications met the inclusion criteria. Of the 35 applicants who listed membership in Alpha Omega Alpha, four (11%) were not listed on the organization's web site as inductees. Of the 464 articles reported as published or in press, only 387 (83%) could be verified. Of the 148 applicants who reported at least one published or in press article, 44 (30%) had at least one unverifiable publication. On multivariable analysis, only male gender increased the likelihood of unverifiable ("ghost") publications (odds ratio 2.1, 95% confidence interval 1.1-4.1). Of the 282 manuscripts reported as submitted or in progress, only 126 (45%) were published. Of the 124 applicants who reported at least one submitted or in progress manuscript, 88 (71%) had at least one unverifiable manuscript. CONCLUSION: The proportion of unverifiable publications listed on gynecologic oncology fellowship applications is concerning. Stringent review of applications before interview invitations and match list submission is warranted.