- Open Access
Cellular and molecular regulation of the primate endometrium: a perspective
© Okulicz; licensee BioMed Central Ltd. 2006
Published: 9 October 2006
This contribution will trace some of the many seminal studies on the female uterus (endometrium) over the centuries and conclude with a description of some current research initiatives in our laboratory. Numerous contributions from many investigators over the years have contributed to our current understanding of endometrial function. The historical section of this chapter is intended to be a brief overall description of some of these efforts and not exhaustive. Additional information can be found in the review articles and books cited herein.
For many centuries studies on the uterus were hampered by both religion and law. Early physicians were forbidden to dissect human bodies and as such their understanding of the female reproductive system was founded on their knowledge of domestic animals . There is, however, some anecdotal evidence from Strabo that the ancient Egyptians (B.C.) performed ovariotomies (ovariectomies) on human females  although this did not apparently impact knowledge of uterine form or function. In the fourth century B.C. Greece, the Hippocratic Corpus represented in large part the beginning of modern medicine (Hippocrates, 460–377 B.C., Father of Medicine). In this work the uterus is described as a number of cavities and horns with no mention of tubes or ovaries. Only the external portions of the female reproductive tract were clearly, carefully, and accurately described. Also during this period, Aristotle described the uterus (in his writings, no drawings available) as a bicornuate structure based on his knowledge of domestic animals e.g. cow.
Rome became the next center for medical and scientific studies on the human. Galen (130–200 A.D.) was the central figure in this effort. His contributions to uterine anatomy and function were minimal and based primarily on the previous work and opinions of Rufus and Aristotle. Of interest is that Galen did study monkeys. Galen's impact as an authority on medical knowledge and practice was enormous and influenced medicine throughout the Middle Ages. During these Dark Ages (lasting through the next millennium) medical and scientific studies on the anatomy and physiology of the uterus were scant. Knowledge in this area relied on the interpretation of past writings and previous opinions which were most often incorrect.
During this period Vesalius stood as the world's premier anatomist with his publication of De humani corporis fabrica in 1543. His work is widely regarded as revolutionary in anatomical science. He studied the uterus and corrected and added important modifications to its anatomy. These important observations included: it contains a single cavity; and included both muscular and decidual layers. In his treatise Fabrica, Vesalius first used the terms uterus and pelvis! His most famous student was Fallopio of Modena who coined the term corpus luteum (previously ovarian humor) and is perhaps best known for the designation, "fallopian" tubes.
The development of the compound microscope, tissue fixatives and stains coupled with access to human female reproductive tissues dramatically improved our understanding of the anatomy and cellular composition of the uterus over the next several centuries. During this period much advancement was made in the understanding that "internal secretions" and chemical mediators (messengers) played major roles in the regulation of internal organs. The hypotheses and evidence for the existence of these factors became accepted. In his Croonian lecture in 1905 at the Royal College of Physicians, "On the Chemical Correlation of the Functions of the Body", Professor Ernest H. Starling first used the word 'hormone' (from the Greek, meaning to excite or arouse) to describe these chemical messengers .
The above immunohistochemical approaches allowed the identification of potential estrogen responsive cells versus unresponsive cells in a variety of tissues that contain heterogeneous cell populations and were not amenable to steroid binding assays. For example, this approach has been applied clinically as a diagnostic tool, specifically breast cancer biopsy specimens, to help identify estrogen responsive cells/tumors [42–44]. In the following years antibodies to the progesterone receptor became widely available and spawned a number of studies on the human and primate endometrium [36, 39, 41, 45–47].
New Initiatives and Approaches
There are a number of approaches that have been used in the past to describe and analyze the hormonal influences and mechanisms that govern primate endometrial responses. These have included: gross anatomy, morphology, and histology; hormonal manipulation; steroid binding assays; immunohistochemical analyses (see above). Transmission and scanning electron microscopy as well as ultrasound have also been used to study uterine (endometrial) structure [14, 50–52]. A number of new and powerful cellular and molecular techniques have recently been added to our arsenal of approaches to study tissue and cell-type gene and protein expression. These include: PCR analysis of gene expression; differential display; gene microarray analyses; laser capture microdissection; and proteomic analysis. Our laboratory has recently embarked on new studies of the rhesus monkey endometrium with several of these molecular approaches and we present some of our recent work below.
This chapter has attempted to provide an historical perspective on the progress of our knowledge of the primate endometrium. This account and the early and recent historical citations echo the truism that all of us as investigators learn from and "stand on the shoulders" of those who have preceded us. Although ideas and concepts have, for the most part, driven our scientific inquiry, some "opinions" do not easily fall out of favor e.g. female testes and will continue to require our vigilant scrutiny. Some new approaches that have been developed and used to investigate the primate endometrium have also been noted. The applications of these tools and others yet to be developed will allow our ideas and hypotheses to be tested and lead us down new pathways of discovery and knowledge.
The author thanks Drs. C. Longcope and C.I. Ace and Charlene Franz for their help and support of this work. This work was supported in part by a grant from the NICHD (HD-31520, WCO).
This article has been published as part of Reproductive Biology and Endocrinology Volume 4, Supplement 1, 2006: Basic and applied biology of the primate reproductive tract: in honor of the career of Dr Robert M Brenner. The full contents of the supplement are available online at http://www.rbej.com/supplements/4/S1.
- Ramsey EM: History. Biology of the Uterus. Edited by: Wynn RM. 1977, New York and London: Plenum Press, 1-18.View ArticleGoogle Scholar
- Medvei CM: A History of Endocrinology. Edited by: Hingham MA. 1982, MTP PressGoogle Scholar
- Young WC: Edgar Allen. Sex and Internal Secretions. Edited by: Young WC, Corner GW. 1961, Baltimore: Williams & Wilkins, xiii-xix.Google Scholar
- Allen E, Doisy EA: The extraction and some properties of an ovarian hormone. J Biol Chem. 1924, 61: 7-27.Google Scholar
- Allen E, Doisy EA: The induction of a sexually mature condition in immature females by injection of the ovarian follicular hormone. Am J Physiol. 1924, 69: 577-588.Google Scholar
- Allen E, Doisy EA: An ovarian hormone. J Am Med Assoc. 1923, 81: 819-821.View ArticleGoogle Scholar
- Allen E: The menstrual cycle of the monkey, macacus rhesus observations on normal animals, the effects of removal of the ovaries and the effects of injections of ovarian and placental extracts into the spayed animals. Contrib Embryol Carnegie Inst. 1927, 19: 1-44.Google Scholar
- Corner GW, Allen W, Myron W: Physiology of the corpus luteum (II). Production of a special reaction progestational proliferation, by extracts of the corpus luteum. Am J Physiol. 1929, 88: 326-339.Google Scholar
- Corner GW, Allen W, Myron W: Normal growth and implantation of embryos after very early ablation of the ovaries, under the influence of extracts of the corpus luteum. Am J Physiol. 1929, 88: 340-346.Google Scholar
- Corner GW: Our knowledge of the menstrual cycle, 1910–1950. Lancet. 1951, 1: 919-923. 10.1016/S0140-6736(51)92447-6.View ArticlePubMedGoogle Scholar
- Markee JE: Menstruation in intraocular endometrial explants in the rhesus monkey. Contrib Embryol Carnegie Inst. 1940, 28: 219-308.Google Scholar
- Bartelmez GW, Corner GW, Hartman CG: Cyclic changes in the endometrium of the rhesus monkey (Macaca mulatta). Contrib Embryol. 1951, 34: 101-144.Google Scholar
- Padykula HA, Coles LG, Okulicz WC, Rapaport SI, McCracken JA, King NW, Longcope C, Kaiserman-Abramof IR: The basalis of the primate endometrium: A bifunctional germinal compartment. Biol Reprod. 1989, 40: 681-690. 10.1095/biolreprod40.3.681.View ArticlePubMedGoogle Scholar
- Padykula HA, Coles LG, McCracken JA, King NW, Longcope C, Kaiserman-Abramof IR: A zonal pattern of cell proliferation and differentiation in the rhesus endometrium during the estrogen surge. Biol Reprod. 1984, 31: 1103-1118. 10.1095/biolreprod31.5.1103.View ArticlePubMedGoogle Scholar
- Hartman CG: Regeneration of the monkey uterus after surgical removal of endometrium and accidental endometriosis. W J Surg Obstet Gynecol. 1944, 52: 87-102.Google Scholar
- Padykula HA: Regeneration in the primate uterus: The role of stem cells. Ann NY Acad Sci. 1991, 622: 47-56.View ArticlePubMedGoogle Scholar
- Ferenczy A: Regeneration of the human endometrium. Progress in Surgical Pathology. Edited by: Fenoglio CM, Wolff M. 1980, Masson Publishing, 157-173.Google Scholar
- Okulicz WC: Regeneration. The Endometrium. Edited by: Glasser SR, Aplin JD, Giudice L, Tabibzadeh S. 2002, Reading, Bershire UK: Harwood Academic Publishers, 110-120.Google Scholar
- Jensen EV, Greene GL, Closs LE, DeSombre ER, Nadji M, Nadji M: Receptors Reconsidered: A 20-year Perspective. Recent Prog Horm Res. 1982, 38: 1-34.PubMedGoogle Scholar
- Jensen EV, Jacobson HI: Fate of steroid estrogens in target tissue. Biological Activities of Steroids in Relation to Cancer. Edited by: Pincus G, Vollmer EP. 1960, New York: Academic Press, 161-178.View ArticleGoogle Scholar
- Gorski J: A hindsight view of early studies on the estrogen receptor: A personal history. Steroids. 1994, 59: 240-243. 10.1016/0039-128X(94)90107-4.View ArticlePubMedGoogle Scholar
- McKenna NJ, Lanz RB, O'Malley BW: Nuclear receptor coregulators: Cellular and molecular biology. Endocr Rev. 1999, 20: 321-344. 10.1210/er.20.3.321.PubMedGoogle Scholar
- McDonnell DP, Norris JD: Connections and regulation of the human estrogen receptor. Science. 2002, 296: 1642-1644. 10.1126/science.1071884.View ArticlePubMedGoogle Scholar
- O'Malley BW: A life-long search for the molecular pathways of steroid hormone action. Mol Endocrinol. 2005, 19: 1402-1411. 10.1210/me.2004-0480.View ArticlePubMedGoogle Scholar
- Norris JD, McDonnell DP: Estrogen receptor pathway. Sci Stke Connection Map. 2005, 22-23.Google Scholar
- Zhang WH, Andersson S, Cheng GJ, Simpson ER, Warner M, Gustafsson JÅ: Update on estrogen signaling. FEBS Lett. 2003, 546: 17-24. 10.1016/S0014-5793(03)00601-X.View ArticleGoogle Scholar
- Watson CS, Campbell CH, Gametchu B: The dynamic and elusive membrane estrogen receptor-α. Steroids. 2002, 67: 429-437. 10.1016/S0039-128X(01)00172-6.View ArticlePubMedGoogle Scholar
- Walters MR, Nemere I: Receptors for steroid hormones: membrane-associated and nuclear forms. Cell Mol Life Sci. 2004, 61: 2309-2321. 10.1007/s00018-004-4065-4.View ArticlePubMedGoogle Scholar
- Greene GL, Fitch FW, Jensen EV: Monoclonal antibodies to estrophilin. Probes for the study of estrogen receptors. Proc Natl Acad Sci USA. 1980, 77: 157-161. 10.1073/pnas.77.1.157.PubMed CentralView ArticlePubMedGoogle Scholar
- Press MF, Nousek-Goebl N, King WJ, Herbst AL, Greene GL: Immunohistochemical assessment of estrogen receptor distribution in the human endometrium throughout the menstrual cycle. Lab Invest. 1984, 51: 495-503.PubMedGoogle Scholar
- McClellan MC, West NB, Tacha DE, Greene GL, Brenner RM: Immunocytochemical localization of estrogen receptors in the macaque reproductive tract with monoclonal antiestrophilins. Endocrinology. 1984, 114: 2002-2014.View ArticlePubMedGoogle Scholar
- Welshons WV, Lieberman ME, Gorski J: Nuclear localization of unoccupied oestrogen receptors. Nature. 1984, 307: 747-749. 10.1038/307747a0.View ArticlePubMedGoogle Scholar
- West NB, Brenner RM: Progesterone-mediated suppression of estradiol receptors in cynomolgus macaque cervix endometrium, and oviduct during sequential estradiol-progesterone treatment. J Steroid Biochem. 1985, 22: 29-37. 10.1016/0022-4731(85)90138-4.View ArticlePubMedGoogle Scholar
- Okulicz WC, Savasta AM, Hoberg LM, Longcope C: Biochemical and immunohistochemical analyses of estrogen and progesterone receptors in the rhesus monkey uterus during the proliferative and secretory phases of artificial menstrual cycles. Fertil Steril. 1990, 53: 913-920.PubMedGoogle Scholar
- Clark JH, Peck EJ: Female Sex Steroids. Receptors and Function. 1979, New York: Springer-VerlagView ArticleGoogle Scholar
- Okulicz WC, Hild-Petito S, Chilton B: Expression of Steroid Hormone Receptors in the Pregnant Uterus. The Endocrinology of Pregnancy. Edited by: Bazer FW, Totowas, NJ. 1998, Humana Press IncGoogle Scholar
- McClellan MC, West NB, Brenner RM: Immunocytochemical localization of estrogen receptors in the macaque endometrium during the luteal-follicular transition. Endocrinology. 1986, 119: 1467-1475.View ArticleGoogle Scholar
- Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS: Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab. 1988, 67: 334-340.View ArticlePubMedGoogle Scholar
- Hild-Petito S, Verhage HG, Fazleabas AT: Immunocytochemical localization of estrogen and progestin receptors in the baboon (Papio anubis) uterus during implantation and pregnancy. Endocrinology. 1992, 130: 2343-2353. 10.1210/en.130.4.2343.PubMedGoogle Scholar
- Okulicz WC, Balsamo M, Tast J: Progesterone regulation of endometrial estrogen receptor and cell proliferation during the late proliferative and secretory phase in artificial menstrual cycles in the rhesus monkey. Biol Reprod. 1993, 49: 24-32. 10.1095/biolreprod49.1.24.View ArticlePubMedGoogle Scholar
- Lessey BA, Yeh IT, Castelbaum AJ, Fritz MA, Ilesanmi AO, Korzeniowski P, Sun JH, Chwalisz K: Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation. Fertil Steril. 1996, 65: 477-483.PubMedGoogle Scholar
- Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD: Immunohistochemical determination of oestrogen receptor: Comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer. 1996, 74: 1445-1451.PubMed CentralView ArticlePubMedGoogle Scholar
- Harvey JM, Clark GM, Osborne CK, Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999, 17: 1474-1481.PubMedGoogle Scholar
- Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller I, Walker R, UK RG, UK NEQA, Scottish Breast Canc Pathol Grp, Receptor Biomarker Study Grp EORTC: Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol. 2000, 53: 634-635. 10.1136/jcp.53.8.634.PubMed CentralView ArticlePubMedGoogle Scholar
- Press MF, Udove JA, Greene GL: Progesterone receptor distribution in the human endometrium. Am J Pathol. 1988, 131: 112-124.PubMed CentralPubMedGoogle Scholar
- Brenner RM, McClellan MC, West NB, Novy MJ, Haluska GJ, Sternfeld MD: Estrogen and progestin receptors in the macaque endometrium. Ann NY Acad Sci. 1991, 622: 149-166.View ArticlePubMedGoogle Scholar
- Okulicz WC, Scarrell R: Estrogen receptor alpha and progesterone receptor (A/B) in the rhesus endometrium during the late secretory phase and menses. Proc Soc Exp Biol Med. 1998, 218: 316-321.View ArticlePubMedGoogle Scholar
- Hodgen GD: Surrogate embryo transfer combined with estrogen-progesterone therapy in monkeys. Implantation, gestation, and delivery without ovaries. JAMA. 1983, 250: 2167-2171. 10.1001/jama.250.16.2167.View ArticlePubMedGoogle Scholar
- Enders AC: Blastocyst II. Implantation in Primates. The Endometrium. Edited by: Glasser SAJGLTS. 2002, Reading, Bershire: Harwood Academic Publishers, 341-351.Google Scholar
- Blankenship TN, Enders AC: Modification of uterine vasculature during pregnancy in macaques. Microsc Res Tech. 2003, 60: 390-401. 10.1002/jemt.10277.View ArticlePubMedGoogle Scholar
- Bhartiya D, Bajpai VK: Cyclic alterations in rhesus monkey endometrium by scanning electron microscopy. Reprod Fertil Dev. 1995, 7: 1199-1207. 10.1071/RD9951199.View ArticlePubMedGoogle Scholar
- Morgan PM, Hutz RJ, Kraus EM, Bavister BD: Ultrasonographic assessment of the endometrium in rhesus monkeys during the normal menstrual cycle. Biol Reprod. 1987, 36: 463-469. 10.1095/biolreprod36.2.463.View ArticlePubMedGoogle Scholar
- Longcope C, Bourget C, Meciak PA, Okulicz WC, McCracken JA, Hoberg LM, Padykula HA: Estrogen dynamics in the female rhesus monkey. Biol Reprod. 1988, 39: 561-565. 10.1095/biolreprod39.3.561.View ArticlePubMedGoogle Scholar
- Okulicz WC, Balsamo M, Tast J: Progesterone regulation of endometrial estrogen receptor and proliferation during the late proliferative and secretory phase in artificial menstrual cycles in the rhesus monkey. Biol Reprod. 1993, 49: 24-32. 10.1095/biolreprod49.1.24.View ArticlePubMedGoogle Scholar
- Okulicz WC, Ace CI, Longcope C, Tast J: Analysis of differential gene regulation in adequate versus inadequate secretory-phase endometrial complementary deoxyribonucleic acid populations from the rhesus monkey. Endocrinology. 1996, 137: 4844-4850. 10.1210/en.137.11.4844.PubMedGoogle Scholar
- Okulicz WC, Ace CI: Temporal regulation of gene expression during the expected window of receptivity in the rhesus monkey endometrium. Biol Reprod. 2003, 69: 1593-1599. 10.1095/biolreprod.103.017525.View ArticlePubMedGoogle Scholar
- Liang P, Pardee A: Differential display of eukaryotic messenger RNA by means of polymerase chain reaction. Science. 1992, 257: 967-971. 10.1126/science.1354393.View ArticlePubMedGoogle Scholar
- Ace CI, Okulicz WC: Identification of progesterone-dependent mRNA regulatory patterns in the rhesus monkey endometrium by differential display reverse-transcriptase-polymerase chain reaction. Biol Reprod. 1999, 60: 1029-1035. 10.1095/biolreprod60.4.1029.View ArticlePubMedGoogle Scholar
- Okulicz WC, Ace CI: Progesterone-regulated gene expression in the primate endometrium. Semin Reprod Endocrinol. 1999, 17: 241-255.View ArticlePubMedGoogle Scholar
- Kao LC, Tulac S, Lobo S, Imani B, Yang JP, Germeyer A, Osteen K, Taylor RN, Lessey BA, Giudice LC: Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002, 143: 2119-2138. 10.1210/en.143.6.2119.View ArticlePubMedGoogle Scholar
- Carson DD, Lagow E, Thathiah A, Al-Shami R, Farach-Carson MC, Vernon M, Yuan L, Fritz MA, Lessey B: Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol Hum Reprod. 2002, 8: 871-879. 10.1093/molehr/8.9.871.View ArticlePubMedGoogle Scholar
- Borthwick JM, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillops SC, Smith SK: Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003, 9: 19-33. 10.1093/molehr/gag004.View ArticlePubMedGoogle Scholar
- Riesewijk A, Martin J, van Os R, Horcajadas JA, Polman J, Pellicer A, Mosselman S, Simon C: Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol Hum Reprod. 2003, 9: 253-264. 10.1093/molehr/gag037.View ArticlePubMedGoogle Scholar
- Ace CI, Okulicz WC: Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol. 2004, 2 (54): 1-9.Google Scholar
- Mirkin S, Nikas G, Hsiu JG, Díaz J, Oehninger S: Gene expression profiles and structural/functional features of the peri-implantation endometrium in natural and gonadotropin-stimulated cycles. J Clin Endocr Metab. 2004, 89: 5742-5752. 10.1210/jc.2004-0605.View ArticlePubMedGoogle Scholar
- Okulicz WC, Ace CI, Franz C: Temporal regulation of endometrial genes during inadequate secretory phases in the Rhesus monkey. Biol Reprod [special issue]. 2005, 114-Google Scholar
- Torres MST, Ace CI, Okulicz WC: Assessment and application of laser microdissection for analysis of gene expression in the Rhesus monkey endometrium. Biol Reprod. 2002, 67: 1067-1072. 10.1095/biolreprod67.4.1067.View ArticlePubMedGoogle Scholar
- Okulicz WC, Ace CI, Torres MS: Gene expression in the rhesus monkey endometrium: differential display and laser capture microdissection. Front Biosci. 2003, 8: d551-d558.View ArticlePubMedGoogle Scholar
- Abu JI, Konje JC: Leukotrienes in gynaecology: the hypothetical value of anti-leukotriene therapy in dysmenorrhoea and endometriosis. Hum Reprod Update. 2000, 6: 200-205. 10.1093/humupd/6.2.200.View ArticlePubMedGoogle Scholar
- Malathy PV, Cheng HC, Dey SK: Production of leukotrienes and prostaglandins in the rat uterus during peri-implantation period. Prostaglandins. 1986, 32: 605-614. 10.1016/0090-6980(86)90042-0.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.