Publications by authors named "Terrence D Lewis"

9 Publications

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NAV3, a Tumor Suppressor Gene, Is Decreased in Uterine Leiomyoma Tissue and Cells.

Reprod Sci 2020 03 1;27(3):925-934. Epub 2020 Jan 1.

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.

NAV 3 is a tumor suppressor of unknown function in leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine leiomyomas. NAV3 protein expression was examined in patient leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry. NAV3 mRNA and protein expression was assessed in leuprolide acetate- and cetrorelix-treated cell line leiomyoma samples. RNAseq analysis of placebo-treated leiomyoma compared with myometrium demonstrated the presence of transcripts encoding for several neuronal proteins. For NAV3, RNA sequence analysis demonstrated decreased expression in leiomyoma as compared with myometrium (0.86 ± 0.03 fold). Presence of NAV3 mRNA was also decreased in leiomyoma surgical samples (0.43 fold ± 0.05, p = 0.026) compared with patient-matched myometrium. Confirmatory qRT-PCR results on immortalized leiomyoma and myometrial cell lines similarly demonstrated a decrease in expression of NAV3 in leiomyomas (0.28 ± 0.02, p = 0.00075). Immunohistochemical analysis demonstrated a significant decrease in NAV 3 protein in leiomyomas (H-score 154.7 ± 6.2) as compared with myometrium (H-score; 312.5 ± 14.7, p < 0.0001). Leuprolide acetate-treated leiomyoma cells demonstrated an increase in NAV 3 mRNA expression (1.53 ± 0.13, p < 0.0001). Similarly, Western blot analysis on leuprolide-treated leiomyoma cells showed a non-significant increase in NAV 3 protein expression (1.26 ± 0.09, p = 0.063). NAV 3, a tumor suppressor in numerous cancers, is decreased in leiomyoma cells and tissue compared with myometrium, and increased by GnRH analog treatment, suggesting that NAV3 may mediate steroid hormone-independent leiomyoma regulation by GnRH analogs.
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http://dx.doi.org/10.1007/s43032-019-00096-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539815PMC
March 2020

Ulipristal acetate decreases active TGF-β3 and its canonical signaling in uterine leiomyoma via two novel mechanisms.

Fertil Steril 2019 04 11;111(4):806-815.e1. Epub 2019 Mar 11.

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Program in Reproductive Endocrinology and Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Electronic address:

Objective: To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study.

Design: Laboratory study.

Setting: University.

Intervention(s): Exposure of leiomyoma cell lines to UPA.

Main Outcome Measure(s): RNAseq was performed on matched myometrium and leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively.

Result(s): In surgical specimen, mRNA for TGF-β3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo leiomyomas compared with myometrium. Analysis of leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-β3 (0.64 ± 0.12-fold), p-TGFR2 (0.56 ± 0.23-fold), pSmad 2 (0.54 ± 0.04-fold), and pSmad 3 (0.65 ± 0.09-fold) compared with untreated leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in leiomyoma treated with UPA (1.48 ± 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings.

Conclusion(s): TGF-β pathway is highly up-regulated in leiomyoma and is directly responsible for development of the fibrotic phenotype. UPA attenuates this pathway by reducing TGF-β3 message and protein expression, resulting in a reduction in TGF-β canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-β complexes. Therefore, UPA inhibits leiomyoma fibrosis by decreasing active TGF-β3 and diminishing signaling through the canonical pathway.

Clinical Trial Registration Number: NCT00290251.
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http://dx.doi.org/10.1016/j.fertnstert.2018.12.026DOI Listing
April 2019

Ulipristal Acetate Mediates Decreased Proteoglycan Expression Through Regulation of Nuclear Factor of Activated T-Cells (NFAT5).

Reprod Sci 2019 02 19;26(2):184-197. Epub 2018 Dec 19.

1 Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Nuclear factor of activated T-cells (NFAT5) is a tissue specific, osmoadaptive transcription factor essential for the control of hydration homeostasis in mammalian cells. Nuclear factor of activated T-cells regulates osmolyte transporters aldo-keto reductase family 1 member B1 (AKR1B1) and solute carrier family 5 member 3 (SLC5A3) to maintain fluid equilibrium in cells. The osmotic potential of the extracellular matrix of leiomyomas is attributed to the role of proteoglycans. In leiomyoma cells, NFAT5 is overexpressed compared to myometrial cells. The selective progesterone receptor modulator, ulipristal acetate, has been reported to decrease the size of leiomyomas in clinical trials. When treated with ulipristal acetate, both patient leiomyoma tissue and leiomyoma cells grown in 3-dimensional cultures show a decrease in the expression of NFAT5 protein, solute transporters AKR1B1 and SLC5A3, and results in an associated decline in the expression of proteoglycans, versican, aggrecan, and brevican. In summary, ulipristal acetate induces changes in leiomyoma cell osmoregulation which result in a decrease in proteoglycan expression.
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http://dx.doi.org/10.1177/1933719118816836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728567PMC
February 2019

A Comprehensive Review of the Pharmacologic Management of Uterine Leiomyoma.

Biomed Res Int 2018 28;2018:2414609. Epub 2018 Jan 28.

Program in Adult & Reproductive Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA.

Uterine leiomyomata are the most common benign tumors of the gynecologic tract impacting up to 80% of women by 50 years of age. It is well established that these tumors are the leading cause for hysterectomy with an estimated total financial burden greater than $30 billion per year in the United States. However, for the woman who desires future fertility or is a poor surgical candidate, definitive management with hysterectomy is not an optimal management plan. Typical gynecologic symptoms of leiomyoma include infertility, abnormal uterine bleeding (AUB)/heavy menstrual bleeding (HMB) and/or intermenstrual bleeding (IMB) with resulting iron-deficiency anemia, pelvic pressure and pain, urinary incontinence, and dysmenorrhea. The morbidity caused by these tumors is directly attributable to increases in tumor burden. Interestingly, leiomyoma cells within a tumor do not rapidly proliferate, but rather the increase in tumor size is secondary to production of an excessive, stable, and aberrant extracellular matrix (ECM) made of disorganized collagens and proteoglycans. As a result, medical management should induce leiomyoma cells toward dissolution of the extracellular matrix, as well as halting or inhibiting cellular proliferation. Herein, we review the current literature regarding the medical management of uterine leiomyoma.
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http://dx.doi.org/10.1155/2018/2414609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893007PMC
October 2018

Progesterone luteal support after ovulation induction and intrauterine insemination: an updated systematic review and meta-analysis.

Fertil Steril 2017 Apr 24;107(4):924-933.e5. Epub 2017 Feb 24.

Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Walter Reed National Military Medical Center, Bethesda, Maryland.

Objective: To evaluate the effect of progesterone (P) for luteal phase support after ovulation induction (OI) and intrauterine insemination (IUI).

Design: An updated systematic review and meta-analysis.

Setting: Not applicable.

Patient(s): Patients undergoing OI-IUI for infertility.

Intervention(s): Exogenous P luteal support after OI-IUI.

Main Outcome Measure(s): Live birth.

Result(s): Eleven trials were identified that met inclusion criteria and constituted 2,842 patients undergoing 4,065 cycles, more than doubling the sample size from the previous meta-analysis. In patients receiving gonadotropins for OI, clinical pregnancy (relative risk [RR] 1.56, 95% confidence interval [CI] 1.21-2.02) and live birth (RR 1.77, 95% CI 1.30-2.42) were more likely in P supplemented patients. These findings persisted in analysis of live birth per IUI cycle (RR 1.59, 95% CI 1.24-2.04). There were no data on live birth in clomiphene citrate or clomiphene plus gonadotropin cycles. There was no benefit on clinical pregnancy with P support for patients who underwent OI with clomiphene (RR 0.85, 95% CI 0.52-1.41) or clomiphene plus gonadotropins (RR 1.26, 95% CI 0.90-1.76).

Conclusion(s): Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins.
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http://dx.doi.org/10.1016/j.fertnstert.2017.01.011DOI Listing
April 2017

Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.

Fertil Steril 2013 Nov 19;100(5):1373-80. Epub 2013 Jul 19.

Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Electronic address:

Objective: To evaluate the effect of luteal phase P support after ovulation induction IUI.

Design: A systematic review and meta-analysis.

Setting: Not applicable.

Patient(s): Undergoing ovulation induction IUI.

Intervention(s): Any form of exogenous P in ovulation induction IUI cycles.

Main Outcome Measure(s): Clinical pregnancy and live birth.

Result(s): Five trials were identified that met inclusion criteria and comprised 1,298 patients undergoing 1,938 cycles. Clinical pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.15-1.98) and live birth (OR 2.11, 95% CI 1.21-3.67) were more likely in P-supplemented patients. These findings persisted in analyses evaluating per IUI cycle, per patient, and first cycle only data. In subgroup analysis, patients receiving gonadotropins for ovulation induction had the most increase in clinical pregnancy with P support (OR 1.77, 95% CI 1.20-2.6). Conversely, patients receiving clomiphene citrate (CC) for ovulation induction showed no difference in clinical pregnancy with P support (OR 0.89, 95% CI 0.47-1.67).

Conclusion(s): Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUI cycles. Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction.
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http://dx.doi.org/10.1016/j.fertnstert.2013.06.034DOI Listing
November 2013

Genistein effects on stromal cells determines epithelial proliferation in endometrial co-cultures.

Exp Mol Pathol 2011 Jun 31;90(3):257-63. Epub 2011 Jan 31.

Department of Pathology and Laboratory Medicine, 620 Brinkhous-Bullitt Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA.

Background: Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers.

Methods: The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively.

Results: Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture.

Conclusions: Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention.
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http://dx.doi.org/10.1016/j.yexmp.2011.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092029PMC
June 2011

Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium.

Obstet Gynecol 2007 Jul;110(1):146-54

Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Objective: To compare the expression of Cyr61 in normal cycling endometrium with endometrium from women with polycystic ovarian syndrome (PCOS) and endometrial hyperplasia and adenocarcinoma.

Methods: This is a retrospective study of 59 samples of normal and abnormal endometrium. Endometrial biopsies were obtained from normal fertile controls throughout the menstrual cycle and compared with endometrium from ovulatory and anovulatory women with PCOS and complex endometrial hyperplasia and endometrioid adenocarcinoma. Cyr61 expression was evaluated by using immunohistochemistry and reverse transcription PCR for Cyr61, estrogen receptor (ER)-alpha, a marker of cell proliferation (Ki67), and another marker of early estrogen action, cFos. Regulation of Cyr61 protein was studied in a steroid-responsive endometrial carcinoma cell line, ECC1.

Results: Cyr61 protein was regulated by estrogen. In normal endometrium, Cyr61 was highest in the proliferative phase and lowest in the normal midsecretory phase. In contrast, elevated levels of Cyr61, ER-alpha, Ki67, and cFos were all found in the midsecretory endometrium of ovulatory PCOS patients, endometrial cancer patients, and hyperplasia patients.

Conclusion: Cyr61 is overexpressed in PCOS endometrium, reflecting a heightened responsiveness to estrogen. As a unique marker of estrogen action, Cyr61 may be an early biomarker for the development of hyperplasia or adenocarcinoma in this group of women.
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http://dx.doi.org/10.1097/01.AOG.0000269047.46078.28DOI Listing
July 2007

Regulation of sensitivity to TRAIL by the PTEN tumor suppressor.

Vitam Horm 2004 ;67:409-26

Lineberger Comprehensive Cancer Center, Department of Medicine and Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.

The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis preferentially in cancer cells is attractive for its development as a novel cancer therapeutic agent, but many cancer cell lines are resistant to TRAIL. While the molecular basis for TRAIL resistance is not always clear, a number of factors have been proposed to mediate TRAIL resistance, including decoy receptor, c-FLIP, nuclear factor (NF)-kappaB, and activation of antiapoptotic kinase signaling. Many growth factor receptors mediate their survival signals through the pathway involving recruitment and activation of phosphatidylinositol (PI) 3-kinase and the serine?threonine kinase Akt. The PTEN tumor suppressor is a phosphatase that dephosphorylates the phospholipids phosphorylated by PI-3 kinase, thereby opposing the action of PI 3-kinase, and acts as the primary negative regulator of the PI-3 kinase?Akt pathway in the cell. Loss of PTEN function occurs frequently in human tumors and leads to constitutive activation of Akt in cancer cells. Constitutively active Akt protects cells from TRAIL-induced apoptosis in multiple tumor types. Growth factors such as epidermal growth factor or insulin-like growth factor-1 also inhibit TRAIL-induced apoptosis through the Akt pathway. Akt exerts its antiapoptotic function by its ability to phosphorylate many key components of the cellular apoptotic regulatory circuit, such as BAD, MDM2, FOXO Forkhead transcription factors, and PED?PEA-15 as well as by its role in activating NF-kappaB. Because PTEN loss is common in tumors, strategies to inactivate Akt may be necessary to overcome TRAIL resistance and make TRAIL-based therapy more effective.
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http://dx.doi.org/10.1016/S0083-6729(04)67021-XDOI Listing
July 2004