The Campion Fund - Resources

Current Research

One of the primary goals of the Leppert Foundation is the provide and sponsor research that will lead to healthier lives, pregnancies, and births. Research conducted by members of our board of directors is published in peer-reviewed journals and presented at conferences nationwide.

“Feeling the force” in reproduction: Mechanotransduction in reproductive processes.
Janice P. Evans, Phyllis C. Leppert

Reproductive biologists are well-versed in many types of biochemical signaling, and indeed, there are almost innumerable examples in reproduction, including steroid and peptide hormone signaling, receptor-ligand and secondary messenger-mediated signaling, signaling regulated by membrane channels, and many others. Among reproductive scientists, a perhaps lesser-known but comparably important mode of signaling is mechanotransduction: the concept that cells can sense and respond to externally applied or internally generated mechanical forces. Given the cell shape changes and tissue morphogenesis events that are components of many phenomena in reproductive function, it should be no surprise that mechanotransduction has major impacts in reproductive health and pathophysiology. The conference on “Mechanotransduction in the Reproductive Tract” was a valuable launch pad to bring this hot issue in development, cell biology, biophysics, and tissue regeneration to the realm of reproductive biology. The goal of the meeting was to stimulate interest and increased mechanotransduction research in the reproductive field by presenting a broad spectrum of responses impacted by this process. The meeting highlighted the importance of convening expert investigators, students, fellows, and young investigators from a number of research areas resulting in cross-fertilization of ideas and suggested new avenues for study. The conference included talks on tissue engineering, stem cells, and several areas of reproductive biology, from uterus and cervix to the gametes. Specific reproductive health-relevant areas, including uterine fibroids, gestation and parturition, and breast tissue morphogenesis, received particular attention.

Treatment for uterine fibroids: Searching for effective drug therapies
Darlene K. Taylor, Phyllis C. Leppert
Drug Discovery Today: Therapeutic Strategies, 2012

Uterine fibroids are common reproductive-age benign tumors that contribute to severe morbidity and infertility. Cumulative incidence is 4 times higher in African- Americans compared to Caucasians and constitutes a major health disparity challenge. Fibroids are the lead- ing indication for hysterectomy and their management averages $21 billion annually in the US. No long term minimally invasive therapies exist. Thus, promising drug therapies, their chemistry, pharmacology, and clinical efficacy, focusing first on innovative drug delivery approaches, are reviewed.

Myometrial Hyperplasia Mimics the Clinical Presentation of Uterine Fibroids: A Report of 3 Cases
Patricia M. Newcomb, M.D., Stewart F. Cramer, M.D., and Phyllis C. Leppert, M.D., Ph.D.
International Journal of Gynecological Pathology, 2013

The clinical diagnosis of fibroid uterus is based on physical examination findings and/or ultrasound. However, it is not uncommon for routine pathology examination to report no significant fibroids in such cases. Myometrial hyperplasia (MMH) is a structural variation with irregular zones of hypercellularity and increased nucleus/cell ratio that appears in adolescence, can progress during the childbearing years, and can sometimes cause grossly detectable bulges on pathologic examination.

Mechanical homeostasis is altered in uterine leiomyoma
Rebecca Rogers, BS; John Norian, MD; Minnie Malik, PhD; Gregory Christman, MD; Mones Abu-Asab, PhD; Faye Chen, PhD; Casey Korecki, MSME; James Iatridis, PhD; William H. Catherino, MD, PhD; Rocky S. Tuan, PhD; Namisha Dhillon; Phyllis Leppert, MD, PhD; James H. Segars, MD
American Journal of Obstetrics & Gynecology, 2008

Uterine leiomyoma produce an extracellular matrix (ECM) that is abnormal in its volume, content, and structure. Alterations in ECM can modify mechanical stress on cells and lead to activation of Rho-dependent signaling and cell growth. Here we sought to determine whether the altered ECM that is produced by leiomyoma was accompanied by an altered state of mechanical homeostasis.

The estimated annual cost of uterine leiomyomata in the United States
Eden R. Cardozo, MD; Andrew D. Clark, MD, PhD; Nicole K. Banks, MD; Melinda B. Henne, MD, MS; Barbara J. Stegmann, MD, MPH; James H. Segars, MD
American Journal of Obstetrics & Gynecology, 2012

The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications.

Characterization of tissue biomechanics and mechanical signaling in 2 uterine leiomyoma
John M. Norian, Carter M. Owen, Juan Taboas, Casey Korecki, Rocky Tuan, Minnie Malik, William H. Catherino, James H. Segars
Matrix Biology (2011)

Leiomyoma are common tumors arising within the uterus that feature excessive deposition of a stiff, disordered 31 extracellularmatrix (ECM).Mechanical stress is a critical determinant of excessive ECMdeposition and increased 32 mechanical stress has been shown to be involved in tumorigenesis. Here we tested the viscoelastic properties of 33 leiomyoma and characterized dynamic and static mechanical signaling in leiomyoma cells using three ap- 34 proaches, including measurement of active RhoA.

Recent Publications on Uterine Leiomyoma

Recent Publications on the Topic of Treatments for Uterine Leiomyoma

Treatment for Uterine Fibroids: Searching for Effective Drug Therapies
Taylor D, Leppert PC.
Drug Discovery Today: Therapeutic Strategies. 2012. 10.1016/jddstr. 2012.06.001; 2012: 9 (1) e41-e49.

This paper includes information regarding all therapies including herbal and traditional Chinese Medicine treatments, with a discussion of the active ingredient in green tea. The pharmacological and biochemical mechanisms of action are also address.

Contemporary management of uterine fibroids: focus on emerging medical treatments.
Singh SS, Belland L.
Curr Med Res Opin 2014 Nov 12 1-12 EPub ahead of print.

The authors reviewed articles published from 1980 to 2012 with a focus on emerging medical therapies. They emphasize their conviction that medical therapies could replace surgical intervention.

Pharmacological treatment of uterine fibroids
Moroni R, Vieria C, Ferriani R, Candido-Dos-Reis F, Brito L.
Ann Med Health Sci Res 2014, S-185 92

A comprehensive review of multiple databases allowed the authors to discuss 41 clinical trials of therapies.

Alternate therapies in management of leiomyomas
Patel A, Malik M, Britten J, Cox J, Catherino WH.
Fertil Steril. 2014, 102:649-655.

The authors present mri-guided focused ultrasound surgery, cryomolysis, inclusion of uterine arteries and discuss procedure techniques, patient eligibility, complications and outcomes.

The impact and management of fibroids for fertility: an evidence based approach
Guo SC, Segars JH.
Obstet Gynecol Clin North Am. 2012, 39:521-533.

This is a paper with good discussions of fertility issues related to leiomyoma management. The authors stress the need for additional treatment options. State that currently myomectomy is the option that is most effective for women desiring pregnancy.

Fibroid growth and medical options for treatment.
Chaubert-Buffet N, Esber N, Bouchard P.
Fertil Steril 2014, 102: 630-639.

Especially good discussions of intrauterine progestin delivery to reduce bleeding, GnRH analogues and selective progesterone receptor modulators are found in this paper.

Uterine morcellation at the time of hysterectomy: techniques, risks, and recommendations.
Stine JE, Clarke-Pearson DL, Gehrig PA.
Obstet Gynecol Sur 2014, 69:415-425.

This paper presents an careful approach to uterine leiomyoma morcellation from the point of view of gynecologic oncologists with specific recommendations. It is important reading for all clinicians who treat women with uterine leiomyoma.

Evidence of biomechanical and collagen heterogeneity in uterine fibroids.
Jayes FL, Liu B, Feng L, et al.
PLOS April 29, 2019

Presents data showing variation in tissue stiffness within one fibroid and between fibroids and the collagen content does not correlate completely with stiffness

Advanced 3D imaging of uterine leiomyoma’s morphology by propagation of phase- contrast microtomography.
Giuliani A, Grecco S, Pacilè S, et al.
Science Reports 2019 7: 10580

Demonstrates the heterogeneity of collagen in uterine fibroids

Selected References for Uterine Fibroid Biology

Evidence of biomechanical and collagen heterogeneity in uterine fibroids.
Jayes FL, Liu B, Feng L, Aviles-Espinoza N, Leikin S, Leppert PC.
PLoS One. 2019 Apr 29;14(4): e0215646. doi: 10.1371/journal.pone.0215646. eCollection 2019.

Bisphenol A induces human uterine leiomyoma cell proliferation through membrane-associated ERα36 via nongenomic signaling pathways.
Yu L, Das P, Vall AJ, Yan Y, Gao X, Sifre MI, Bortner CD, Castro L, Kissling GE, Moore AB, Dixon D.
Mol Cell Endocrinol. 2019 Mar 15;484:59-68. doi: 10.1016/j.mce.2019.01.001. Epub 2019 Jan 4.

The Life Cycle of the Uterine Fibroid Myocyte.
Flake GP, Moore AB, Sutton D, Flagler N, Clayton N, Kissling GE, Hall BW, Horton J, Walmer D, Robboy SJ, Dixon D.
Curr Obstet Gynecol Rep. 2018 Jun;7(2):97-105. doi: 10.1007/s13669-018-0241-7. Epub 2018 Apr 28.

A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells.
Ng SSM, Jorge S, Malik M, Britten J, Su SC, Armstrong CR, Brennan JT, Chang S, Baig KM, Driggers PH, Segars JH.
J Clin Endocrinol Metab. 2019 Mar 1;104(3):970-980. doi:10.1210/jc.2018-01216.

Moving Toward Individualized Medicine for Uterine Leiomyomas.
Laughlin-Tommaso SK, Stewart EA.
Obstet Gynecol. 2018 Oct;132(4): 961-971.doi:10.1097/AOG.0000000000002785.

Proteomic Characterization of the Extracellular Matrix of Human Uterine Fibroids.
Jamaluddin MFB, Nahar P, Tanwar PS.
Endocrinology. 2018 Jul 1;159(7):2656-2669. doi: 10.1210/en.2018-00151.

The Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids (COMPARE-UF) registry: rationale and design.
Stewart EA, Lytle BL, Thomas L, Wegienka GR, Jacoby V, Diamond MP, Nicholson WK, Anchan RM, Venable S, Wallace K, Marsh EE, Maxwell GL, Borah BJ, Catherino WH, Myers ER.
Am J Obstet Gynecol. 2018 Jul;219(1):95.e1-95.e10. doi: 10.1016/j.ajog.2018.05.004. Epub 2018 May 8.

Activin A induces leiomyoma cell proliferation, extracellular matrix (ECM) accumulation and myofibroblastic transformation of myometrial cells via p38 MAPK.
Bao H, Sin TK, Zhang G
Biochem Biophys Res Commun. 2018 Oct 2;504(2):447-453. doi: 10.1016/j.bbrc.2018.08.171. Epub 2018 Sep 5.

Vitamin D and Uterine Fibroids-Review of the Literature and Novel Concepts.
Ciebiera M, Włodarczyk M, Ciebiera M, Zaręba K, Łukaszuk K, Jakiel G.
Int J Mol Sci. 2018 Jul 14;19(7). pii: E2051. doi: 10.3390/ijms19072051.

MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma.
Cardozo ER, Foster R, Karmon AE, Lee AE, Gatune LW, Rueda BR, Styer AK.
Reprod Biol Endocrinol. 2018 May 11;16(1):46. doi: 10.1186/s12958-018-0364-8.

Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells.
Prusinski Fernung LE, Yang Q, Sakamuro D, Kumari A, Mas A, Al-Hendy A.
Biol Reprod. 2018 Oct 1;99(4):735-748. doi: 10.1093/biolre/ioy097.

Clinical, pathologic, cytogenetic, and molecular profiling in self-identified black women with uterine leiomyomata.
Hayden MA, Ordulu Z, Gallagher CS, Quade BJ, Anchan RM, Middleton NR, Srouji SS, Stewart EA, Morton CC.
Cancer Genet. 2018 Apr;222-223:1-8. doi: 10.1016/j.cancergen.2018.01.001. Epub 2018 Feb 19.

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence.
D'Souza AL, Chevillet JR, Ghanouni P, Yan X, Tewari M, Gambhir SS.
PLoS One. 2018 Mar 16;13(3): e0194268. doi: 10.1371/journal.pone.0194268. eCollection 2018.

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19.
Park MJ, Shen H, Spaeth JM, Tolvanen JH, Failor C, Knudtson JF, McLaughlin J, Halder SK, Yang Q, Bulun SE, Al-Hendy A, Schenken RS, Aaltonen LA, Boyer TG.
J Biol Chem. 2018 Mar 30;293(13):4870-4882. doi: 10.1074/jbc.RA118.001725. Epub 2018 Feb 13.

Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases.
Kamel M, Wagih M, Kilic GS, Diaz-Arrastia CR, Baraka MA, Salama SA.
Biomed Res Int. 2017; 2017:5316845. doi: 10.1155/2017/5316845. Epub 2017 Sep 10.

Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids.
Ko YA, Jamaluddin MFB, Adebayo M, Bajwa P, Scott RJ, Dharmarajan AM, Nahar P, Tanwar PS.
Reproduction. 2018 Jan;155(1):61-71. doi: 10.1530/REP-17-0339. Epub 2017 Oct 24.

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma.
Wu X, Serna VA, Thomas J, Qiang W, Blumenfeld ML, Kurita T.
Cancer Res. 2017 Dec 15;77(24):6891-6901. doi: 10.1158/0008-5472.CAN-17-1744. Epub 2017 Oct 20.

Literature Review on the Role of Uterine Fibroids in Endometrial Function.
Ikhena DE, Bulun SE.
Reprod Sci. 2018 May;25(5):635-643. doi: 10.1177/1933719117725827. Epub 2017 Aug 22.

Multiple clinical characteristics separate MED12-mutation-positive and -negative uterine leiomyomas.
Heinonen HR, Pasanen A, Heikinheimo O, Tanskanen T, Palin K, Tolvanen J, Vahteristo P, Sjöberg J, Pitkänen E, Bützow R, Mäkinen N, Aaltonen LA.
Sci Rep. 2017 Apr 21;7(1):1015. doi: 10.1038/s41598-017-01199-0.

Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays.
Yatsenko SA, Mittal P, Wood-Trageser MA, Jones MW, Surti U, Edwards RP, Sood AK, Rajkovic A.
Fertil Steril. 2017 Feb;107(2):457-466.e9. doi: 10.1016/j.fertnstert.2016.10.035. Epub 2016 Nov 23.

Angiogenesis and Vascularization of Uterine Leiomyoma: Clinical Value of Pseudocapsule Containing Peptides and Neurotransmitters.
Tinelli A, Mynbaev OA, Sparic R, Vergara D, Di Tommaso S, Salzet M, Maffia M, Malvasi A.
Curr Protein Pept Sci. 2017;18(2):129-139. doi: 10.2174/1389203717666160322150338.

A Proteomic Analysis of Human Uterine Myoma.
Rizzello A, Franck J, Pellegrino M, De Nuccio F, Simeone P, Fiore G, Di Tommaso S, Malvasi A, Tinelli A, Fournier I, Salzet M, Maffia M, Vergara D.
Curr Protein Pept Sci. 2017;18(2):167-174. doi: 10.2174/1389203717666160322150603.

Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production.
Marsh EE, Steinberg ML, Parker JB, Wu J, Chakravarti D, Bulun SE.
Fertil Steril. 2016 Sep 1;106(3):766-72. doi: 10.1016/j.fertnstert.2016.05.001. Epub 2016 May 24.

Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle.
Stewart EA, Friedman AJ, Peck K, Nowak, RA.
J Clin Endocrin Metabol. 1994: 79 (3): 900-06.

Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma.
Norian JM, Owen CM, Taboas J, Korecki C, Tuan R Malik M, Catherino WH Segars JH.
Matrix Biology. 2012: 31 (1): 57-65.

Ultrastructure of Collagen Fibrils in Uterine Leiomyomas and Normal Myometrium.
Leppert PC Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH.
Fertil Steril. 2004: 82: Supp 3: 1182-87.

A comparative analysis of structure and spatial distribution of decorin in human leiomyoma and normal myometrium.
Berto AG, Sampaio LO, Franco CR, Cesar RM, Jr, Michelacci YM.
Biochim Biophys Acta. 2003: 1619 (1): 98-112.

Stem cells in the myometrium and in myomas.
Maruyama T, Ono M, Yoshimura Y.
Seminars Reprod Med. 2013: 30 (01): 077-081.Thieme Medical Publishers

Vitamin D3 inhbits expression and activation of matrix metalloproteinase-2 and -9 in human uterine fibroid cells.
Halder SK, Osteen KG, Al-Hendy A.
Hum Reprod. 2013: 28(9) 2407-16.

Vitamin D and the risk of uterine fibroids.
Baird DD, Hill MC, Schectman JM, Holis BW.
Epidemiology. 2013: 24(3): 447-53.

Growth of uterine leiomyomata among premenopausal black and white women.
Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, Semelka RC, Kowalik A, Armao D, Davis B, Baird DD.
PNAS US. 2008:105: 50: 19887-92.

Gene expression in uterine leiomyoma from tumors likely to be growing (from black women over 35) and tumors likely to be non-growing (from white women over 35.
Davis BJ, Risinger JI, Chandramouli GV, Bushel PR, Baird DD, Peddada SD.
PLoS One. 2013: 8 (6): e63909.

The estimated annual cost of uterine leiomyomata in the United States.
Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH.
Am J Obstet Gynecol. 2011: 206 (3) 211.e1-9.

Leiomyoma; genetics, assisted reproduction, pregnancy and therapeutic advances.
Levy G, Hill MJ, Beall S, Zarek, SM Segars JH, Catherino W.
J Assist Reprod Genetics. 2012: 29(8) 703-12.