Hindawi Publishing Corporation Obstetrics and Gynecology International Volume 2013, Article ID 528376, 20 pages http://dx.doi.org/10.1155/2013/528376 Research Article The Natural History of Uterine Leiomyomas: Light and Electron Microscopic Studies of Fibroid Phases, Interstitial Ischemia, Inanosis, and Reclamation Gordon P. Flake, 1 Alicia B. Moore, 2 Deloris Sutton, 1 Grace E. Kissling, 3 John Horton, 1 Benita Wicker, 1 David Walmer, 4 Stanley J. Robboy, 4 and Darlene Dixon 2 1 Cellular and Molecular Pathology Branch, National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services, Research Triangle Park, NC 27709, USA 2 Molecular Pathogenesis Group, National Toxicology Program Laboratory (NTPL), National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services, Research Triangle Park, NC 27709, USA 3 Biostatistics Branch, National Toxicology Program (NTP), Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services, Research Triangle Park, NC 27709, USA 4 Duke University Medical Center, Durham, NC 27710, USA Correspondence should be addressed to Darlene Dixon; dixon@niehs.nih.gov Received 5 March 2013; Revised 26 June 2013; Accepted 30 July 2013 Academic Editor: Pasquapina Ciarmela Copyright © 2013 Gordon P. Flake et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We propose, and ofer evidence to support, the concept that many uterine leiomyomas pursue a self-limited life cycle. his cycle can be arbitrarily divided on the basis of morphologic assessment of the collagen content into 4 phases: (1) proliferation, (2) proliferation and synthesis of collagen, (3) proliferation, synthesis of collagen, and early senescence, and (4) involution. Involution occurs as a result of both vascular and interstitial ischemia. Interstitial ischemia is the consequence of the excessive elaboration of collagen, resulting in reduced microvascular density, increased distance between myocytes and capillaries, nutritional deprivation, and myocyte atrophy. he end stage of this process is an involuted tumor with a predominance of collagen, little to no proliferative activity, myocyte atrophy, and myocyte cell death. Since many of the dying cells exhibit light microscopic and ultrastructural features that appear distinct from either necrosis or apoptosis, we refer to this process as inanosis, because it appears that nutritional deprivation, or inanition, is the underlying cause of cell death. he disposal of myocytes dying by inanosis also difers in that there is no phagocytic reaction, but rather an apparent dissolution of the cell, which might be viewed as a process of reclamation as the molecular contents are reclaimed and recycled. 1. Introduction he etiology of uterine leiomyomas (or ibroids) is unknown, and their pathogenesis has been incompletely determined. Because they are so common (80% in African-American women and 70% in Caucasian women in one study [1]), it would be reasonable to assume that women share a common risk factor for the development of ibroids. One such factor is menstruation, and perhaps more importantly is the occurrence of dysmenorrhea with associated abnormal uterine contractions [2, 3], which is estimated to occur in up to 70% of women by the ith year ater menarche [4]. Patients with primary dysmenorrhea experience varied patterns of myometrial hyperactivity, including contractions of increased amplitude, very frequent contractions, and/or a high basal tone, and this increased contractile activity is associated with a reduction in uterine blood low [5]. If focal injury (ischemic or otherwise) to the myometrium occurs during menstruation, the reparative response could be similar to that which occurs following injury to blood vessels. In response to vascular intimal injury, smooth muscle cells of the media migrate into the intima, proliferate, and synthesize