Role of Progesterone in Nonhuman Primate Implantation

ABSTRACT

Herein we review the morphological and physiological effects of estradiol and progesterone (P) on the nonhuman primate uterus. Progesterone action acts to prepare the endometrium for embryo implantation, which normally occurs only during a brief period in the mid-luteal phase of the menstrual cycle. During this window of implantation, P stimulates secretory morphological differentiation and suppresses estrogen receptor α (ERα), in the endometrial functionalis zone. Reduced endometrial ERα is a definitive physiological marker for the onset of endometrial receptivity in primates. These actions of P are specific for the functionalis zones, and P does not fully inhibit ERα in the glands of basalis zone of nonhuman primates. Paradoxically, during the secretory phase of the cycle, progesterone receptor (PR) is also reduced in the glandular epithelium of the progestin-responsive functionalis zone. Therefore, P action on the epithelium in the functionalis zone may be mediated by paracrine factors arising from the PR-positive cells in the stroma. Genomic analysis of the endometrium of women and nonhuman primates has revealed numerous secretory phase genes that may contribute to differentiation of the endometrium. However, the exact nature and function of these putative factors have been elusive. We propose that nonhuman primates, especially macaques, can provide a valuable animal model for experimentally testing the functional role of P-regulated genes on endometrial receptivity.

KEYWORDS

Macaque - endometrium - secretory differentiation - progesterone

REFERENCES

• 1 Nardo L G, Sallam H N. Progesterone supplementation to prevent recurrent miscarriage and to reduce implantation failure in assisted reproduction cycles.  Reprod Biomed Online. 2006;  13(1) 47-57
• 2 Simón C, Martin J C, Pellicer A. Paracrine regulators of implantation.  Baillieries Best Pract Res Clin Obstet Gynaecol. 2000;  14(5) 815-826
• 3 Lessey B A. Adhesion molecules and implantation.  J Reprod Immunol. 2002;  55(1-2) 101-112
• 4 Brenner R M, Slayden O D. Cyclic changes in the primate oviduct and endometrium. In: Knobil E, Neill JD The Physiology of Reproduction. New York; Raven Press 1994: 541-569
• 5 Gilardi K V, Shideler S E, Valverde C R, Roberts J A, Lasley B L. Characterization of the onset of menopause in the rhesus macaque.  Biol Reprod. 1997;  57(2) 335-340
• 6 Navot D, Laufer N, Kopolovic J et al.. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries.  N Engl J Med. 1986;  314 806-811
• 7 Ghosh D, Sengupta J. Endometrial responses to a deciduogenic stimulus in ovariectomized rhesus monkeys treated with oestrogen and progesterone.  J Endocrinol. 1989;  120 51-58
• 8 Hodgen G D. Surrogate embryo transfer combined with estrogen-progesterone therapy in monkeys.  JAMA. 1983;  250 2167-2171
• 9 Slayden O D, Brenner R M. 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
• 10 Brenner R M, Slayden O D. Steroid receptors in blood vessels of the rhesus macaque endometrium: a review.  Arch Histol Cytol. 2004;  67(5) 411-416
• 11 Rudolph-Owen L A, Slayden O D, Matrisian L M, Brenner R M. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients.  Biol Reprod. 1998;  59(6) 1349-1359
• 12 Ace C I, Okulicz W C. Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase.  Reprod Biol Endocrinol. 2004;  2 54
• 13 Slayden O D, Chwalisz K, Brenner R M. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques.  Hum Reprod. 2001;  16(8) 1562-1574
• 14 Bartelmez G W. Cyclic changes in the endometrium of the rhesus monkey (Macaca mulatta).  Contrib Embryol. 1951;  34 99-144
• 15 Bartelmez G W. The phases of the menstrual cycle and their interpretation in terms of the pregnancy cycle.  Am J Obstet Gynecol. 1957;  74 931-955
• 16 Ferenczy A. Surface ultrastructural response of the human uterine lining epithelium to hormonal environment. A scanning electron microscopic study.  Acta Cytol. 1977;  21 566-572
• 17 Chan R WS, Schwab K E, Gargett C E. Clonogenicity of human endometrial epithelial and stromal cells.  Biol Reprod. 2004;  70 1738-1750
• 18 Noyes R W, Hertig A T, Rock J. Dating the endometrial biopsy.  Fertil Steril. 1950;  1 3-25
• 19 Noyes R W. The underdeveloped secretory endometrium.  Am J Obstet Gynecol. 1959;  77 929-945
• 20 Murray M J, Meyer W R, Zaino R J 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
• 21 Batista M C, Cartledge T P, Merino M J et al.. Midluteal phase endometrial biopsy does not accurately predict luteal function.  Fertil Steril. 1993;  59 294-300
• 22 McClellan M, West N B, Brenner R M. Immunocytochemical localization of estrogen receptors in the macaque endometrium during the luteal-follicular transition.  Endocrinology. 1986;  119 2467-2475
• 23 Nayak N R, Brenner R M. Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium.  J Clin Endocrinol Metab. 2002;  87(4) 1845-1855
• 24 Slayden O D, Brenner R M. RU 486 action after estrogen priming in the endometrium and oviducts of rhesus monkeys (Macaca mulatta).  J Clin Endocrinol Metab. 1994;  78 440-448
• 25 Ace C I, Okulicz W C. Differential gene regulation by estrogen and progesterone in the primate endometrium.  Mol Cell Endocrinol. 1995;  115 95-103
• 26 Okulicz W C, Ace C I. Temporal regulation of gene expression during the expected window of receptivity in the rhesus monkey endometrium.  Biol Reprod. 2003;  69(5) 1593-1599
• 27 Brenner R M, Slayden O D, Rodgers W H 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
• 28 Lydon J P, DeMayo F J, Conneely O M, O'Malley B W. Reproductive phenotypes of the progesterone receptor null mutant mouse.  J Steroid Biochem Mol Biol. 1996;  56 67-77
• 29 Lydon J P, DeMayo F J, Funk C R et al.. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.  Genes Dev. 1995;  9 2266-2278
• 30 Mangal R K, Wiehle R D, Poindexter III A N, Weigel N L. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle.  J Steroid Biochem Mol Biol. 1997;  63(4-6) 195-202
• 31 Bethea C L, Widmann A A. Differential expression of progestin receptor isoforms in the hypothalamus, pituitary, and endometrium of rhesus macaques.  Endocrinology. 1998;  139(2) 677-687
• 32 Tseng L, Zhu H H. Regulation of progesterone receptor messenger ribonucleic acid by progestin in human endometrial stromal cells.  Biol Reprod. 1997;  57(6) 1360-1366
• 33 Mulac-Jericevic B, Conneely O M. Reproductive tissue selective actions of progesterone receptors.  Reproduction. 2004;  128(2) 139-146
• 34 Mulac-Jericevic B, Mullinax R A, DeMayo F J, Lydon J P, Conneely O. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.  Science. 2000;  289(9) 1751-1754
• 35 Chwalisz K, Garg R, Brenner R, Slayden O, Winkel C, Elger W. Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs).  Reprod Biol Endocrinol. 2006;  9(4 suppl 1) S8
• 36 Slayden O D, Zelinski-Wooten M B, Chwalisz K, Stouffer R L, Brenner R M. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct.  Hum Reprod. 1998;  13(2) 269-277
• 37 Slayden O D, Nayak N R, Burton K A et al.. Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.  J Clin Endocrinol Metab. 2001;  86(6) 2668-2679
• 38 Slayden O D, Hirst J J, Brenner R M. Estrogen action in the reproductive tract of rhesus monkeys during antiprogestin treatment.  Endocrinology. 1993;  132(4) 1845-1856
• 39 Critchley H OD, Brenner R M, Drudy T A, Williams K, Groome N P, Saunders P TK. Oestrogen receptor beta (ER beta) is uniquely expressed by the vascular endothelium of the human and non-human primate endometrium.  J Endocrinol. 2000;  167(suppl) 69
• 40 Critchley H OD, Brenner R M, Henderson T A 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
• 41 Enders A C. Current topic: structural responses of the primate endometrium to implantation.  Placenta. 1991;  12 309-325
• 42 Rosario G X, Modi D N, Sachdeva G, Manjramkar D D, Puri C P. 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
• 43 Fazleabas A T, Hild-Petito S, Verhage H G. Secretory proteins and growth factors of the baboon (Papio anubis) uterus: potential roles in pregnancy.  Cell Biol Int. 1994;  18 1145-1153
• 44 Kessler C A, Moghadam K K, Schroeder J K, Buckley A R, Brar A K, Handwerger S. Cannabinoid receptor I activation markedly inhibits human decidualization.  Mol Cell Endocrinol. 2005;  229(1-2) 65-74
• 45 Lessey B A, Palomino W A, Apparao K, Young S L, Lininger R A. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women.  Reprod Biol Endocrinol. 2006;  9(4 suppl 1) S9
• 46 Schiessl B, Mylonas I, Kuhn C et al.. Expression of estrogen receptor-alpha, estrogen receptor-beta and placental endothelial and inducible NO synthase in intrauterine growth-restricted and normal placentals.  Arch Med Res. 2006;  37(8) 967-975
• 47 Salamonsen L A, Nagase H, Woolley D E. Matrix metalloproteinases and their tissue inhibitors at the ovine trophoblast-uterine interface.  J Reprod Fertil Suppl. 1995;  49 29-37
• 48 Blankenship T N, Enders A C. Trophoblast cell-mediated modifications to uterine spiral arteries during early gestation in the macaque.  Acta Anat (Basel). 1997;  158(4) 227-236
• 49 Slayden O D, Rubin J S, Lacey D L, Brenner R M. Effects of keratinocyte growth factor in the endometrium of rhesus macaques during the luteal-follicular transition.  J Clin Endocrinol Metab. 2000;  85(1) 275-285
• 50 Izumi S, Slayden O D, Rubin J S, Brenner R M. Keratinocyte growth factor and its receptor in the rhesus macaque placenta during the course of gestation.  Placenta. 1996;  17 123-135
• 51 Garfield R E, Saade G, Buhimschi C et al.. Control and assessment of the uterus and cervix during pregnancy and labour.  Hum Reprod Update. 1998;  4 673-695
• 52 Frears E R, Zhang Z, Blake D R, O'Connell J P, Winyard P G. Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite.  FEBS Lett. 1996;  381(1-2) 21-24
• 53 Zhang J, Salamonsen L A. Tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3 in human endometrium during the menstrual cycle.  Mol Hum Reprod. 1997;  3(9) 735-741
• 54 Wang H, Li Q, Shao L, Zhu C. Expression of matrix metalloproteinase-2, -9, -14, and tissue inhibitors of metalloproteinase-1, -2, -3 in the endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy.  Biol Reprod. 2001;  65(1) 31-40
• 55 Gao F, Chen X L, Wei P, Gao H J, Liu Y X. Expression of matrix metalloproteinase-2, tissue inhibitors of metalloproteinase-1, -3 at the implantation site of rhesus monkey during the early stage of pregnancy.  Endocrine. 2001;  16(1) 47-54
• 56 Izumi S-I, Slayden O D, Brenner R M. Keratinocyte growth factor (KGF) and its receptor (KGFR) in the placenta of rhesus macaques. Paper presented at: Annual Meeting of the Society for the Study of Reproduction July 9-12, 1995 Davis, CA;
• 57 Koji T, Chedid M, Rubin J S et al.. Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: Keratinocyte growth factor as a progestomedin.  J Cell Biol. 1994;  125(2) 393-401
• 58 Lindsey J S, Brenner R M. Novel hepatocyte growth factor/scatter factor isoform transcripts in the macaque endometrium and placenta.  Mol Hum Reprod. 2002;  8(1) 81-87
• 59 Coutifaris C, Myers E R, Guzick D S et al.. Histological dating of timed endometrial biopsy tissue is not related to fertility status.  Fertil Steril. 2004;  82(5) 1264-1272
• 60 Giudice L C. Elucidating endometrial function in the post-genomic era.  Hum Reprod Update. 2003;  9(3) 223-235
• 61 Giudice L C. Microarray expression profiling reveals candidate genes for human uterine receptivity.  Am J Pharmacogenomics. 2004;  4(5) 299-312
• 62 Gibbs R A, Rogers J, Katze M G et al.. Evolutionary and biomedical insights from the rhesus macaque genome.  Science. 2007;  316(5822) 222-234
• 63 Kao L C, Tulac S, Lobo S et al.. Global gene profiling in human endometrium during the window of implantation.  Endocrinology. 2002;  143(6) 2119-2138
• 64 Kao L C, Germeyer A, Tulac S et al.. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility.  Endocrinology. 2003;  144(7) 2870-2881
• 65 Horcajadas J A, Pellicer A, Simón C. Wide genomic analysis of human endometrial receptivity: new times, new opportunities.  Hum Reprod Update. 2007;  13(1) 77-86
• 66 Torres M S, Ace C I, Okulicz W C. Assessment and application of laser microdissection for analysis of gene expression in the rhesus monkey endometrium.  Biol Reprod. 2002;  67(4) 1067-1072
• 67 Nie G, Findlay J K, Salamonsen L A. Identification of novel endometrial targets for contraception.  Contraception. 2005;  71(4) 272-281
• 68 Nie G, Li Y, Wang M, Liu Y X, Findlay J K, Salamonsen L A. Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility.  Biol Reprod. 2005;  72(4) 1029-1036