Faculty Bibliography

RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.

OBJECTIVE: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 mug (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact chi tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

This contribution summarizes the pivotal role of the ovarian renin-angiotensin system (OVRAS) in ovarian physiology and disease, with particular emphasis on human clinical implications and established translational applications. The presence of a complete OVRAS in all studied species has been known for decades. The OVRAS has major effects on follicle development/atresia and ovulation and steroid hormone secretion, that is, it is necessary for normal reproduction. It is well established that OVRAS activity is regulated by gonadotropins and depends on activation of proteases in the area of growing follicles. Angiotensin and angiotensin receptors are widely distributed in the ovarian follicle, preovulatory theca and granulosa cells, and postovulatory mural granulosa-lutein cells and regulate steroidogenesis. Molecular blockade of the OVRAS inhibits oocyte maturation and ovulation. Pathologically abnormal OVRAS function has been associated with infertility, polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), and ovarian cancer. Both hyperandrogenism in PCOS and third space fluid accumulation in OHSS have been convincingly linked to overexpression of renin and angiotensin. Blockade of angiotensin receptors is under study for the treatment of gynecologic cancer, OHSS, and PCOS. However, a full understanding of the OVRAS and translational applications is lacking. In part, this is due to the discovery in recent years of previously unknown renin-angiotensin system (RAS) components and novel functions of "classical" RAS components that remain to be integrated into translational studies; newer, more specific agents to block RAS components are available only now for such research and treatment. The need for further studies is evident.

OBJECTIVE: Dental treatment is often categorized as a moderately or severely painful experience; however, no clinical data reported by the patient and dentist currently exists to support this degree of pain. This has contributed possibly to the overprescribing of analgesics, in particular the opioid class of medications. The primary objective of the study was to document the dentists' postprocedural prescriptions and recommendations for analgesic medications and their effectiveness for a 5-day period. Medications prescribed or recommended in the patient-reported outcomes included: opioid, nonsteroidal anti-inflammatory drugs (NSAIDs), and over-the-counter (OTC) analgesics. Met hods : This study used both dentist and patient responses to evaluate the use of opioid, NSAID, and OTC recommended or prescribed analgesics following one of seven classes of dental procedures encompassing over 22 specific coded procedures thought to elicit pain. The patient-centered study included a 5-day postprocedural patient follow-up assessment of the medication's effectiveness in relieving pain. RESULTS: Baseline questionnaires were completed by 2765 (99.9%) of 2767 eligible patients, and 2381 (86%) patients responded to the Day 5 follow-up questionnaires. CONCLUSION: The data suggest NSAIDs, both OTC and prescribed dosages, may be a sufficient analgesic to treat most postoperative dental pain. Clinical judgment as to the use of an opioid should include the physiological principles related to the pharmacology of pain and inflammation and may include a central effect. ClinicalTrials.gov Identifier: NCT02929602.

Mammals have evolved to nourish their offspring exclusively with maternal milk for around half of the lactation period, a crucial developmental window. In view of oral-breast contact during lactation and the differences in oral microbiota between cesarean section (C-section) and vaginally delivered infants, we expected differences in milk composition by delivery mode. We performed a cross-sectional study of banked human milk and found changes related to time since delivery in bacterial abundance and glycosylation patterns only in milk from women who delivered vaginally. The results warrant further research into the effects of delivery mode on milk microbes, milk glycosylation, and postpartum infant development.

Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.

Although there are many analytical methods available for estimation of metformin in biological samples and pharmaceutical preparations, to our knowledge there is no specific spectrophotometric method using its derivatization by the Mannich reaction. A simple spectrophotometric method was developed by studying the UV evolution of the complex obtained between metformin, formaldehyde and uranine using the Mannich reaction. Measurements of metformin were achieved at 437 nm using UV-visible spectroscopy. To assess the validity of the method in a clinical situation the extraction was adapted to extract metformin from human urine that had been tested by our method. The spectrometric correlation coefficient (R²) was found to be 0.98 over metformin concentrations of 5- 30 mug/mL. This range includes the clinical levels reached during treatment. The method was validated for linearity, accuracy, and precision. The within-assay limit of detection and quantification (sensitivity) were found to be 0.001 mug/mL. This method for quantification of metformin is simple, precise and accurate. It is suitable as an alternative to existing clinical methods and for the analysis of metformin in pharmacodynamic studies of urinary excretion as well as pharmaceutical formulations and in vitro dissolution studies

Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17beta-estradiol (50 mug/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.