Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

Uterine fibroids are the most common gynecologic tumors with a significant medical and financial burden. Several genetic, hormonal, and biological factors have been shown to contribute to the development and growth of fibroid tumors. Of these factors, estrogen is particularly critical since fibroids are considered estrogen dependent because no prepubertal cases have been described in the literature and tumors tend to regress after menopause. Understanding the role of estrogen in fibroids is not only important for understanding the pathobiology of fibroids but also for the development of successful therapeutics. In this review, we discuss the types and structure of estrogen receptors (nuclear and membrane bound, including α and β receptors and G protein-coupled estrogen receptor 1 GPER1). Estrogen-signaling pathways in fibroids include genomic (direct and indirect) and nongenomic including Ras-Raf-MEK (MAPK/Erk Kinase)-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-phosphatidylinositol-3,4,5-trisphosphate (PIP3)-Akt (Protein kinase B)-mammalian target of rapamycin (mTOR) pathways; shortly Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways. Several aberrations in estrogen receptors and signaling pathways are implicated in fibroid pathobiology. Current therapeutic and research agents targeting ERs/signaling include gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, aromatase inhibitors, selective ER modulators, gene therapy, and others. Future research can identify potential targets for the development of novel treatments. In particular, epigenomics of estrogen activity and individualized (precision) medicine appear to be attractive areas for future research.

Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy after tamoxifen withdrawal may reverse tamoxifen-associated endometrial thickening.

BACKGROUND Neoplasms of the pancreas during pregnancy are rare, with less than 25 cases of benign and malignant tumors reported in the literature. METHODS We present three unique cases of pancreatic tumors occurring during pregnancy—one mucinous cystic neoplasm and two adenocarcinomas. We review the literature regarding pancreatic neoplasms during pregnancy and discuss the diagnosis, complications, and management of these tumors. RESULTS MRI and ultrasound are the imaging modalities of choice in pregnancy. In patients with benign or premalignant tumors, surgical resection may be postponed until the second trimester. In symptomatic patients, or if there is a concern for intrauterine growth restriction (IUGR), urgent surgical intervention should be performed. With malignant tumors, the benefit of delaying surgery must be balanced with the risk of maternal disease progression. Termination of the pregnancy should be discussed when a malignant tumor is diagnosed during the first trimester. Pancreatic tumors diagnosed during the third trimester may be resected after delivery. If malignant, early delivery of the fetus and subsequent maternal operation can be considered at appropriate fetal maturity. CONCLUSION When these tumors occur during pregnancy, they present a diagnostic and treatment dilemma, with variation in treatment based on gestational age and patient preference.

Importance Obstetricians and gynecologists frequently deal with hemorrhage so they should be familiar with management of patients who refuse blood transfusion. Although there are some reports in the literature about management of Jehovah’s Witness patients in obstetrics and gynecology, most of them are case reports and a comprehensive review about these patients including ethico-legal perspective is lacking. Objective This review outlines the medical, ethical and legal implications of management of Jehovah’s Witness patients in obstetrical and gynecological settings. Evidence Acquisition A search of published literature using Pubmed, Ovid Medline, EMBASE and Cochrane databases was conducted about physiology of oxygen delivery and response to tissue hypoxia, mortality rates at certain hemoglobin levels, medical management options for anemic patients who refuse blood transfusion and ethical/legal considerations in Jehovah’s Witness patients. Results Early diagnosis of anemia and immediate initiation of therapy is essential in patients who refuse blood transfusion. Medical management options include iron supplementation and erythropoietin. There are also some promising therapies that are in development such as anti-hepcidin antibodies and hemoglobin based oxygen carriers. Options to decrease blood loss include anti-fibrinolytics, desmopressin, recombinant Factor VII and factor concentrates. When surgery is the only option, every effort should be made to pursue minimally invasive approaches. Conclusion and Relevance All obstetricians and gynecologists should be familiar with alternatives and ‘less invasive’ options for patients who refuse blood transfusions. Target Audience Obstetricians and gynecologists, family physicians