To the Editor:
In the context of the excellent Views and Reviews devoted to the endometrium (1), Dr. Bruce A. Lessey offers a thorough analysis of 186 publications that are of significance to the window of implantation (WOI) (2). We feel this already exhaustive effort needs to be expanded further. Although one histological hallmark of midluteal endometrium – pinopodes (whose significance as markers of endometrial receptivity has been questioned) – is reviewed in detail, another, the nucleolar channel system (NCS), went unmentioned. The presence of NCSs distinctly marks the midluteal phase of human endometrium overlapping with the WOI.
NCSs were identified over half a century ago using electron microscopy and can now be readily detected by marker proteins using indirect immunofluorescence (3). These 1-µm-sized organelles are found exclusively in the nuclei of human endometrial epithelial cells of the secretory phase. NCSs are specific to healthy human endometrium, being absent from other hormone-sensitive tissue (such as breast epithelium), from endometrial carcinoma specimens, or from baboon endometrium. The presence of NCSs peaks during cycle days LH+5 to LH+10 (menstrual cycle days 19-24), and subsequently trails off (3,4). NCSs are absent before LH+4, after LH+13 and during the proliferative phase. In fact, their midluteal/WOI presence is so robust that it is independent of fertility status (5).
Despite a lack of functional definition, NCSs are cell biological marvels with a unique protein composition and as membranous organelles in the otherwise membrane-free cell nucleus. Now that they can be easily detected in endometrial biopsy specimens, NCSs should not be discounted as potential markers of the WOI and certainly deserve an honorable mention.
Edward J Nejat, M.D., M.B.A.
Gregory Zapantis, M.D.
Eli A Rybak, M.D., M.P.H.
U. Thomas Meier, Ph.D.
Albert Einstein College of Medicine
Bronx, New York
1. Casper, RF. It’s time to pay attention to the endometrium. Fertility and Sterility 96, 519-521, (2011).
2. Lessey, BA. Assessment of endometrial receptivity. Fertility and Sterility 96, 522-529, (2011).
3. Guffanti E, Kittur N, Brodt ZN, Polotsky AJ, Kuokkanen SM, Heller DS, et al. Nuclear pore complex proteins mark the implantation window in human endometrium. J. Cell Sci. 121, 2037-2045, (2008).
4. More IA, McSeveney D. The three dimensional structure of the nucleolar channel system in the endometrial glandular cell: serial sectioning and high voltage electron microscopic studies. J Anat 130, 673-682, (1980).
5. Rybak EA, Szmyga, MJ, Zapantis G, Rausch M, Beshay VE, Polotsky, AJ, et al. The nucleolar channel system reliably marks the midluteal endometrium regardless of fertility status: a fresh look at an old organelle. Fertility and Sterility 95, 1385-1389.e1381, (2011).
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.09.053
The Author Responds:
Thank you for your letter to the editor regarding the new Views and Reviews feature in the September issue of Fertility and Sterility regarding the endometrium.
You note our omission of the nucleolar channel system (NCS) as one of the ultrastructural entities of a receptive endometrium. Indeed there are 22 references on PubMed dating back to 1965 on these fascinating and unique subcellular features of mid-secretory endometrium. I was aware of the NCS during endometrial development and we discussed the potential importance of these structures (complete with photomicrographs) in the latest version of Yen and Jaffe’s textbook in the chapter entitled, “The structure, function and evaluation of the female reproductive tract” (1). It is likely that I left out other favorite endometrial moieties as well, and I apologize to you and everyone else that might find that the article falls short of the mark.
As you point out, the expression pattern of NCS, while present in the mid-secretory phase, is unperturbed in the endometrium of women with unexplained infertility and present regardless of fertility status (2). In thinking about what to include in an article about endometrial receptivity (with too many references), I considered that the ideal biomarker would have functional significance to the process of implantation. By that, I also inferred that the loss of that biomarker would logically be associated with a deficit as evidenced by infertility or pregnancy loss. Since this particular biomarker does not appear to bear that attribute, I did not include it. In thinking about this further in response to your letter, I think it is indeed unusual and even unlikely that a progesterone mediated event (directly or indirectly) (3) would not be affected by endometriosis or other gynaecologic disorders that have been shown to cause progesterone resistance in some women (4). Such a robust biomarker certainly deserves future study and is a feature that might be examined in the luteal phase defect model of endometrial development on which Dr. Steven Young and Dr. Marc Fritz at the University of North Carolina have been working (5). There must be levels of progesterone, below which, the NCS do not correctly assemble or form and this model would certainly address that question.
I hope that readers of this exchange will now go and read more about these interesting structures and appreciate, as I do, the ever-growing complexities and mysteries of the human endometrium.
Bruce A. Lessey, M.D., Ph.D.
Greenville Hospital System
Center for Women’s Medicine
Greenville, South Carolina
1. Strauss JF III, Lessey BA. The structure, function, and evaluation of the female reproductive tract. In: Strauss JF, III, Barbieri RL, eds. Reproductive Endocrinology: Physiology, pathophysiology, and clinical management. Philadelphia, PA: Saunders Elsevier, 2009:191-233.
2. Rybak EA, Szmyga MJ, Zapantis G, Rausch M, Beshay VE, Polotsky AJ et al. The nucleolar channel system reliably marks the midluteal endometrium regardless of fertility status: a fresh look at an old organelle. Fertil Steril;95:1385-9 e1.
3. Kohorn EI, Rice SI, Gordon M. In vitro production of nucleolar channel system by progesterone in human endometrium. Nature 1970;228:671-2.
4. Young SL, Lessey BA. Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med 2010;28:5-16.
5. Young SL, Lessey BA, Balthazar U, Zaino RJ, Jin JP, Sherwin JRA et al. Defining the relationship between progesterone dose, endometrial histology and gene expression using an in vivo luteal phase defect model. Reprod Sci 2011;18:272A.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.09.054