Download PDF
Semin Reprod Med 2014; 32(05): 385-391
DOI: 10.1055/s-0034-1376357
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Cyclic Remodeling of the Nonhuman Primate Endometrium: A Model for Understanding Endometrial Receptivity

Ov Daniel Slayden
1   Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
› Author Affiliations
Further Information

Publication History

Publication Date:
24 June 2014 (online)

    Permissions and Reprints

Abstract

Old World monkeys display physiological responses to steroid hormones that are similar to those of women. In this review, we describe cyclic morphological changes that take place within the uterus of Old World primates during the menstrual cycle. In primates, estrogen stimulates endometrial growth in the follicular phase of the menstrual cycle. Progesterone secreted in the luteal phase acts to induce secretory differentiation, which is required for successful embryo implantation. During the differentiation process, endometrial estrogen receptor-1 (ESR-1) is suppressed, and reduced staining for ESR-1 is a definitive marker of the onset of uterine receptivity. Downregulation of ESR-1 is topographically limited to the functionalis (upper) zones of the endometrium, the zones in which embryo implantation occurs, indicating that zone-specific factors play a role in the differentiation process. Future genomic and proteomic studies are expected to reveal additional markers for diagnosing endometrial receptivity. Due to the distinct zonal response of the endometrium to ovarian steroids, accurate histological characterization will remain necessary to interpret novel targets in the assessment of fertility.

Keywords

menstrual cycle - histology - endometrium - secretory differentiation - progesterone
 

  • References

  • 1 Shively CA, Clarkson TB. The unique value of primate models in translational research. Nonhuman primate models of women's health: introduction and overview. Am J Primatol 2009; 71 (9) 715-721
    CrossrefPubMedGoogle Scholar
  • 2 Brenner RM, Slayden OD. Cyclic changes in the primate oviduct and endometrium. In: Knobil E, Neill JD, , eds. The Physiology of Reproduction. New York: Raven Press; 1994. 2. (10): 541-569
    Google Scholar
  • 3 Slayden OD, Brenner RM. Role of progesterone in the structural and biochemical remodeling of the primate endometrium. Ernst Schering Res Found Workshop 2005; (52) 89-118
    PubMedGoogle Scholar
  • 4 Brenner RM, Slayden OD. Molecular and functional aspects of menstruation in the macaque. Rev Endocr Metab Disord 2012; 13 (4) 309-318
    CrossrefPubMedGoogle Scholar
  • 5 Carroll RL, Mah K, Fanton JW, Maginnis GN, Brenner RM, Slayden OD. Assessment of menstruation in the vervet (Cercopithecus aethiops). Am J Primatol 2007; 69 (8) 901-916
    CrossrefPubMedGoogle Scholar
  • 6 Van Esch E, Buse E, Weinbauer GF, Weinberg CR, Cline JM. The macaque endometrium, with special reference to the Cynomolgus monkey (Macaca fascicularis). Toxicol Pathol 2008; 36: 67S-100S
    CrossrefPubMedGoogle Scholar
  • 7 Kraemer DC, Maqueo M, Hendrickx AG, Vera Cruz NC. Histology of the baboon endometrium during the menstrual cycle and pregnancy. Fertil Steril 1977; 28 (4) 482-487
    PubMedGoogle Scholar
  • 8 Rosario GX, Modi DN, Sachdeva G, Manjramkar DD, Puri CP. Morphological events in the primate endometrium in the presence of a preimplantation embryo, detected by the serum preimplantation factor bioassay. Hum Reprod 2005; 20 (1) 61-71
    PubMedGoogle Scholar
  • 9 Gilardi KV, Shideler SE, Valverde CR, Roberts JA, Lasley BL. Characterization of the onset of menopause in the rhesus macaque. Biol Reprod 1997; 57 (2) 335-340
    CrossrefPubMedGoogle Scholar
  • 10 Nyachieo A, Chai DC, Deprest J, Mwenda JM, D'Hooghe TM. The baboon as a research model for the study of endometrial biology, uterine receptivity and embryo implantation. Gynecol Obstet Invest 2007; 64 (3) 149-155
    CrossrefPubMedGoogle Scholar
  • 11 Molskness TA, Hess DL, Maginnis GM, Wright JW, Fanton JW, Stouffer RL. Characteristics and regulation of the ovarian cycle in vervet monkeys (Chlorocebus aethiops). Am J Primatol 2007; 69 (8) 890-900
    CrossrefPubMedGoogle Scholar
  • 12 Vandevoort CA, Mtango NR, Latham KE, Stewart DR. Primate preimplantation embryo is a target for relaxin during early pregnancy. Fertil Steril 2011; 96 (1) 203-207
    CrossrefPubMedGoogle Scholar
  • 13 VandeVoort CA, Mtango NR, Lee YS, Smith GW, Latham KE. Differential effects of follistatin on nonhuman primate oocyte maturation and pre-implantation embryo development in vitro. Biol Reprod 2009; 81 (6) 1139-1146
    CrossrefPubMedGoogle Scholar
  • 14 Hisaw FL, Hisaw Jr FL. Action of estrogen and progesterone on the reproductive tract of lower primates. In: Young WC, , ed. Sex and Internal Secretions. Baltimore, MD: Lippincott Williams & Wilkins; 1961: 556-589
    Google Scholar
  • 15 Cox KE, Sharpe-Timms KL, Kamiya N, Saraf M, Donnelly KM, Fazleabas AT. Differential regulation of stromelysin-1 (matrix metalloproteinase-3) and matrilysin (matrix metalloproteinase-7) in baboon endometrium. J Soc Gynecol Investig 2000; 7 (4) 242-248
    CrossrefPubMedGoogle Scholar
  • 16 Slayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol 2004; 67 (5) 393-409
    CrossrefPubMedGoogle Scholar
  • 17 Hodgen GD. Surrogate embryo transfer combined with estrogen-progesterone therapy in monkeys. Implantation, gestation, and delivery without ovaries. JAMA 1983; 250 (16) 2167-2171
    CrossrefPubMedGoogle Scholar
  • 18 Ferenczy A. Surface ultrastructural response of the human uterine lining epithelium to hormonal environment. A scanning electron microscopic study. Acta Cytol 1977; 21 (4) 566-572
    PubMedGoogle Scholar
  • 19 Kraemer DC . Comparative assessment of endometrial morphology and function in nonhuman primate models. In: Diczfalusy E, Fraser IS, Webb FTG, eds. Endometrial Bleeding and Steroidal Contraception (Proceedings of a Symposium on Steroid Contraception and Mechanisms of Endometrial Bleeding Organized by WHO, September 12–14, 1979). Bath, England: Pitman Press Ltd.; 1980 :366–383
    PubMed
  • 20 Bartelmez GW. Histological studies on the menstruating mucous membrane of the human uterus. Contrib Embryol 1933; 142: 142-186
    PubMedGoogle Scholar
  • 21 Bartelmez GW. Cyclic changes in the endometrium of the rhesus monkey (Macaca mulatta). Contrib Embryol 1951; 34: 99-144
    PubMedGoogle Scholar
  • 22 Padykula HA, Coles LG, McCracken JA, King Jr 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 (5) 1103-1118
    CrossrefPubMedGoogle Scholar
  • 23 Fusi L, Cloke B, Brosens JJ. The uterine junctional zone. Best Pract Res Clin Obstet Gynaecol 2006; 20 (4) 479-491
    CrossrefPubMedGoogle Scholar
  • 24 Keator CS, Lindner JR, Belcik JT, Bishop CV, Slayden OD. Contrast-enhanced ultrasound reveals real-time spatial changes in vascular perfusion during early implantation in the macaque uterus. Fertil Steril 2011; 95 (4) 1316-1321 , e1–e3
    CrossrefPubMedGoogle Scholar
  • 25 Enders AC. Implantation in the macaque: expansion of the implantation site during the first week of implantation. Placenta 2007; 28 (8-9) 794-802
    CrossrefPubMedGoogle Scholar
  • 26 Enders AC, Blankenship TN, Fazleabas AT, Jones CJ. Structure of anchoring villi and the trophoblastic shell in the human, baboon and macaque placenta. Placenta 2001; 22 (4) 284-303
    CrossrefPubMedGoogle Scholar
  • 27 Markee JE. The morphological and endocrine basis for menstrual bleeding. In: Meigs JV, Surgis SH, , eds. Progress in Gynecology. New York: Grune & Stratton; 1950: 63-74
    Google Scholar
  • 28 Lydon JP, DeMayo FJ, Conneely OM, O'Malley BW. Reproductive phenotypes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol 1996; 56 (1–6, Spec No) 67-77
    CrossrefPubMedGoogle Scholar
  • 29 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 (4) 2343-2353
    CrossrefPubMedGoogle Scholar
  • 30 Noel SD, Keen KL, Baumann DI, Filardo EJ, Terasawa E. Involvement of G protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol Endocrinol 2009; 23 (3) 349-359
    CrossrefPubMedGoogle Scholar
  • 31 Keator CS, Mah K, Slayden OD. Alterations in progesterone receptor membrane component 2 (PGRMC2) in the endometrium of macaques afflicted with advanced endometriosis. Mol Hum Reprod 2012; 18 (6) 308-319
    CrossrefPubMedGoogle Scholar
  • 32 Brenner RM, Slayden OD. Steroid receptors in blood vessels of the rhesus macaque endometrium: a review. Arch Histol Cytol 2004; 67 (5) 411-416
    CrossrefPubMedGoogle Scholar
  • 33 Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950; 1: 3-25
    PubMedGoogle Scholar
  • 34 Noyes RW. The underdeveloped secretory endometrium. Am J Obstet Gynecol 1959; 77 (5) 929-945
    PubMedGoogle Scholar
  • 35 Murray MJ, Meyer WR, Zaino RJ , et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 2004; 81 (5) 1333-1343
    CrossrefPubMedGoogle Scholar
  • 36 Batista MC, Cartledge TP, Merino MJ , et al. Midluteal phase endometrial biopsy does not accurately predict luteal function. Fertil Steril 1993; 59 (2) 294-300
    PubMedGoogle Scholar
  • 37 Rudolph-Owen LA, Slayden OD, Matrisian LM, Brenner RM. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients. Biol Reprod 1998; 59 (6) 1349-1359
    CrossrefPubMedGoogle Scholar
  • 38 Markee JE. Menstruation in intraocular endometrial transplants in the rhesus monkey. Contrib Embryol 1940; 177: 219-308
    PubMedGoogle Scholar
  • 39 Nayak NR, Brenner RM. Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium. J Clin Endocrinol Metab 2002; 87 (4) 1845-1855
    CrossrefPubMedGoogle Scholar
  • 40 Kreitmann-Gimbal B, Goodman AL, Bayard F, Hodgen GD. Characterization of estrogen and progesterone receptors in monkey endometrium: methodology and effects of estradiol and/or progesterone on endometrium of castrate monkeys. Steroids 1979; 34 (7) 749-770
    CrossrefPubMedGoogle Scholar
  • 41 Chan RWS, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 2004; 70 (6) 1738-1750
    CrossrefPubMedGoogle Scholar
  • 42 Brenner RM, Slayden OD, Rodgers WH , et al. Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium. Hum Reprod 2003; 18 (6) 1185-1193
    CrossrefPubMedGoogle Scholar
  • 43 Slayden OD, Brenner RM. RU 486 action after estrogen priming in the endometrium and oviducts of rhesus monkeys (Macaca mulatta). J Clin Endocrinol Metab 1994; 78 (2) 440-448
    CrossrefPubMedGoogle Scholar
  • 44 Critchley HOD, Brenner RM, Henderson TA , et al. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab 2001; 86 (3) 1370-1378
    CrossrefPubMedGoogle Scholar
  • 45 Ace CI, Okulicz WC. Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol 2004; 2: 54
    CrossrefPubMedGoogle Scholar
  • 46 Okulicz WC, Ace CI. Temporal regulation of gene expression during the expected window of receptivity in the rhesus monkey endometrium. Biol Reprod 2003; 69 (5) 1593-1599
    CrossrefPubMedGoogle Scholar
  • 47 Critchley HOD, Brenner RM, Drudy TA, Williams K, Groome NP, Saunders PTK. Oestrogen receptor beta (ERb) is uniquely expressed by the vascular endothelium of the human and non-human primate endometrium. J Endocrinol 2000; 167 (Suppl): 69
    PubMedGoogle Scholar
  • 48 Neulen J, Williams RF, Breckwoldt M, Chwalisz K, Baulieu EE, Hodgen GD. Non-competitive anti-oestrogenic actions of progesterone antagonists in primate endometrium: enhancement of oestrogen and progesterone receptors with blockade of post-receptor proliferative mechanisms. Hum Reprod 1996; 11 (7) 1533-1537
    CrossrefPubMedGoogle Scholar
  • 49 Enders AC. Current topic: structural responses of the primate endometrium to implantation. Placenta 1991; 12 (4) 309-325
    CrossrefPubMedGoogle Scholar
  • 50 Fazleabas AT, Hild-Petito S, Verhage HG. Secretory proteins and growth factors of the baboon (Papio anubis) uterus: potential roles in pregnancy. Cell Biol Int 1994; 18 (12) 1145-1153
    CrossrefPubMedGoogle Scholar
  • 51 Brenner RM, Cao WG, Citruk-Ware R, Mah K, Slayden OD, Tsong YY. Zonal differences in hormonal responsiveness during decidualization in the primate endometrium. The Endocrine Society's 88th Annual Meeting, June 24–27, 2006:P2–56
    PubMedGoogle Scholar
  • 52 Moghadam KK, Kessler CA, Schroeder JK, Buckley AR, Brar AK, Handwerger S. Cannabinoid receptor I activation markedly inhibits human decidualization. Mol Cell Endocrinol 2005; 229 (1–2) 65-74
    CrossrefPubMedGoogle Scholar
  • 53 Coutifaris C, Myers ER, Guzick DS , et al; NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004; 82 (5) 1264-1272
    CrossrefPubMedGoogle Scholar
  • 54 Bogan RL, Murphy MJ, Stouffer RL, Hennebold JD. Systematic determination of differential gene expression in the primate corpus luteum during the luteal phase of the menstrual cycle. Mol Endocrinol 2008; 22 (5) 1260-1273
    CrossrefPubMedGoogle Scholar
  • 55 Almeida-Francia CC, Keator CS, Mah K, Holden L, Hergert C, Slayden OD. Localization and hormonal regulation of endometrial matrix metalloproteinase-26 in the rhesus macaque. Hum Reprod 2012; 27 (6) 1723-1734
    CrossrefPubMedGoogle Scholar
  • 56 Torres MS, Ace CI, Okulicz WC. Assessment and application of laser microdissection for analysis of gene expression in the rhesus monkey endometrium. Biol Reprod 2002; 67 (4) 1067-1072
    CrossrefPubMedGoogle Scholar