Ovarian hyperstimulation affects fluid transporters in the uterus: a potential mechanism in uterine receptivity
Laura A. Lindsay A B and Christopher R. Murphy AA Anderson Stuart Bldg, F13, School Of Medical Sciences (Anatomy and Histology), The University of Sydney, NSW 2006, Australia.
B Corresponding author. Email: laural@anatomy.usyd.edu.au
Reproduction, Fertility and Development 26(7) 982-990 https://doi.org/10.1071/RD12396
Submitted: 10 December 2012 Accepted: 25 June 2013 Published: 26 July 2013
Abstract
Controlled ovarian hyperstimulation is commonly used in fertility treatment. Evidence suggests that this could alter the endometrial environment and influence implantation rate. However, the mechanisms underlying this disruption are unknown. A recently developed rat ovarian hyperstimulation (OH) model found alterations in the localisation and expression of several molecules associated with implantation, as well as an increase in luminal fluid at the time of implantation. The present study investigated the effects of OH in rats on the expression of fluid-transporting molecules aquaporin 5 (AQP5) and claudin 4. The expression of these proteins was investigated in uterine luminal epithelial cells of rats undergoing OH and compared with normal pregnancy. There was a significant increase in AQP5 protein in OH rats at the time of implantation, along with a loss of the mesometrial staining gradient, which is thought to contribute to implantation position. At the same time, there was a significant decrease in claudin 4 protein. These results suggest that OH in rats causes a dysregulation in uterine fluid dynamics through modifications to fluid-transporting molecules, resulting in an unfavourable implantation environment for the blastocyst.
Additional keywords: aquaporins, pregnancy, tight junctions.
References
Akman, M. A., Erden, H. F., and Bahceci, M. (2005). Endometrial fluid visualized through ultrasonography during ovarian stimulation in IVF cycles impairs the outcome in tubal factor, but not PCOS, patients. Hum. Reprod. 20, 906–909.| Endometrial fluid visualized through ultrasonography during ovarian stimulation in IVF cycles impairs the outcome in tubal factor, but not PCOS, patients.Crossref | GoogleScholarGoogle Scholar | 15640251PubMed |
Alden, R. H. (1945). Implantation of the rat egg I. Experimental alteration of uterine polarity. J. Exp. Zool. 100, 229–235.
| Implantation of the rat egg I. Experimental alteration of uterine polarity.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaH28%2FitFCqsg%3D%3D&md5=8f693112d8e5f0d480eb6e0a59609c28CAS | 21003385PubMed |
Basir, G. S., O, W. S., Ng, E. H. Y., and Ho, P. C. (2001). Morphometric analysis of peri-implantation endometrium in patients having excessively high oestradiol concentrations after ovarian stimulation. Hum. Reprod. 16, 435–440.
| Morphometric analysis of peri-implantation endometrium in patients having excessively high oestradiol concentrations after ovarian stimulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXislCgt7c%3D&md5=3351e969e89029f3c33a3116a63abcdaCAS | 11228208PubMed |
Bavister, B. D. (2000). Interactions between embryos and the culture milieu. Theriogenology 53, 619–626.
| Interactions between embryos and the culture milieu.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXltlarsw%3D%3D&md5=4a23a031aa7b91c659202b2fde5d8ce4CAS | 10735054PubMed |
Biyiksiz, P. C., Filiz, S., and Vural, B. (2011). Is sildenafil citrate affect endometrial receptivity? An immunohistochemical study. Gynecol. Endocrinol. 27, 767–774.
| Is sildenafil citrate affect endometrial receptivity? An immunohistochemical study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXht12isb%2FI&md5=5485590364fe459d7aab42014c801204CAS | 21190420PubMed |
Bosch, E., Labarta, E., Crespo, J., Simon, C., Remohi, J., Jenkins, J., and Pellicer, A. (2010). Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum. Reprod. 25, 2092–2100.
| Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXptlalt74%3D&md5=15327bd058de9919065791abca329976CAS |
Check, J. H., Lurie, D., Askari, H. A., Hoover, L., and Lauer, C. (1993). The range of subtle rise in serum progesterone levels following controlled ovarian hyperstimulation associated with lower in vitro fertilization pregnancy rates is determined by the source of manufacturer. Eur. J. Obstet. Gynecol. Reprod. Biol. 52, 205–209.
| The range of subtle rise in serum progesterone levels following controlled ovarian hyperstimulation associated with lower in vitro fertilization pregnancy rates is determined by the source of manufacturer.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXktVWhtrg%3D&md5=8bdac814c37458bfe6dd748fdd149b32CAS | 8163037PubMed |
Check, J. H., Hourani, C., Choe, J. K., Callan, C., and Adelson, H. G. (1994). Pregnancy rates in donors versus recipients according to the serum progesterone level at the time of human chorionic-gonadotropin in a shared oocyte program. Fertil. Steril. 61, 262–264.
| 1:STN:280:DyaK2c7jtFSkug%3D%3D&md5=1f0093576a47aa918c0d65bf789cd346CAS | 8299780PubMed |
Check, J. H., Wilson, C., Choe, J. K., Amui, J., and Brasile, D. (2010). Evidence that high serum progesterone (P) levels on day of human chorionic gonadotropin (hCG) injection have no adverse effect on the embryo itself as determined by pregnancy outcome following embryo transfer using donated eggs. Clin. Exp. Obstet. Gynecol. 37, 179–180.
| 1:STN:280:DC%2BC3cbntFOktQ%3D%3D&md5=7b3770f0eb1ab68ca8257676c309fb9eCAS | 21077517PubMed |
Enders, A., and Schlafke, S. (1967). A morphological analysis of the early implantation stages in the rat. Am. J. Anat. 120, 185–225.
| A morphological analysis of the early implantation stages in the rat.Crossref | GoogleScholarGoogle Scholar |
Ertzeid, G., and Storeng, R. (2001). The impact of ovarian stimulation on implantation and fetal development in mice. Hum. Reprod. 16, 221–225.
| The impact of ovarian stimulation on implantation and fetal development in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhsFGrs70%3D&md5=24cdbc6c8185c7c657145ca856072dd6CAS | 11157810PubMed |
Fanchin, R., de Ziegler, D., Taieb, J., Hazout, A., and Frydman, R. (1993). Premature elevation of plasma progesterone alters pregnancy rates of in vitro fertilization and embryo transfer. Fertil. Steril. 59, 1090–1094.
| 1:STN:280:DyaK3s3lt1Wjug%3D%3D&md5=9e9b9db1b708a6641e86b2cf1b47e53aCAS | 8486179PubMed |
Fanchin, R., Righini, C., Olivennes, F., Ferreira, A. L., deZiegler, D., and Frydman, R. (1997). Consequences of premature progesterone elevation on the outcome of in vitro fertilization: insights into a controversy. Fertil. Steril. 68, 799–805.
| Consequences of premature progesterone elevation on the outcome of in vitro fertilization: insights into a controversy.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK1c%2FltFantg%3D%3D&md5=9d34004998749b3c02e85f83d710fe1fCAS | 9389805PubMed |
Finn, C. (1989). Species variation, location and attachment of blastocysts. In ‘Blastocyst Implantation’. (Ed. K. Yoshinaga.) pp. 47–54. (Adams Publishing Group: Boston.)
Fong, S. K., Liu, C. Q., and Chan, H. C. (1998). Cellular mechanisms of adrenaline-stimulated anion secretion by the mouse endometrial epithelium. Biol. Reprod. 59, 1342–1348.
| Cellular mechanisms of adrenaline-stimulated anion secretion by the mouse endometrial epithelium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXnvVKrtr4%3D&md5=bf5f2e66e9606a5e26fc0add077647c3CAS | 9828177PubMed |
Gad, A., Besenfelder, U., Rings, F., Ghanem, N., Salilew-Wondim, D., Hossain, M. M., Tesfaye, D., Lonergan, P., Becker, A., Cinar, U., Schellander, K., Havlicek, V., and Holker, M. (2011). Effect of reproductive tract environment following controlled ovarian hyperstimulation treatment on embryo development and global transcriptome profile of blastocysts: implications for animal breeding and human assisted reproduction. Hum. Reprod. 26, 1693–1707.
| Effect of reproductive tract environment following controlled ovarian hyperstimulation treatment on embryo development and global transcriptome profile of blastocysts: implications for animal breeding and human assisted reproduction.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC3MngtVehtg%3D%3D&md5=c1efd830d1de270419bf465a5d79fec2CAS | 21531990PubMed |
Hildenbrand, A., Lalitkumar, L., Nielsen, S., Gemzell-Danielsson, K., and Stavreus-Evers, A. (2006). Expression of aquaporin 2 in human endometrium. Fertil. Steril. 86, 1452–1458.
| Expression of aquaporin 2 in human endometrium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtlWnurbP&md5=c9b491f3984872d83dd975ae202f7413CAS | 16979638PubMed |
Jovanović, A., and Kramer, B. (2010). The effect of hyperstimulation on transforming growth factor beta(1) and beta(2) in the rat uterus: possible consequences for embryo implantation. Fertil. Steril. 93, 1509–1517.
| The effect of hyperstimulation on transforming growth factor beta(1) and beta(2) in the rat uterus: possible consequences for embryo implantation.Crossref | GoogleScholarGoogle Scholar | 19200954PubMed |
Kaneko, Y., Lindsay, L. A., and Murphy, C. R. (2008). Focal adhesions disassemble during early pregnancy in rat uterine epithelial cells. Reprod. Fertil. Dev. 20, 892–899.
| Focal adhesions disassemble during early pregnancy in rat uterine epithelial cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Oks77E&md5=360f8f3006d062e4dcf237674985b4a6CAS | 19007553PubMed |
Kaneko, Y., Lecce, L., and Murphy, C. R. (2009). Ovarian hormones regulate expression of the focal adhesion proteins, talin and paxillin, in rat uterine luminal but not glandular epithelial cells. Histochem. Cell Biol. 132, 613–622.
| Ovarian hormones regulate expression of the focal adhesion proteins, talin and paxillin, in rat uterine luminal but not glandular epithelial cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhsVWms7%2FK&md5=7583071bced0646c724b72c4119bee55CAS | 19779731PubMed |
Kiliçdag, E. B., Haydardedeoglu, B., Cok, T., Hacivelioglu, S. O., and Bagis, T. (2010). Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles. Arch. Gynecol. Obstet. 281, 747–752.
| Premature progesterone elevation impairs implantation and live birth rates in GnRH-agonist IVF/ICSI cycles.Crossref | GoogleScholarGoogle Scholar | 19862542PubMed |
Krasnow, J. S., Tollerud, D. J., Naus, G., and DeLoia, J. A. (1996). Endometrial Th2 cytokine expression throughout the menstrual cycle and early pregnancy. Hum. Reprod. 11, 1747–1754.
| Endometrial Th2 cytokine expression throughout the menstrual cycle and early pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK28XmsVajt7c%3D&md5=a2d684a4a795b00a0bf60bd9a19440eeCAS | 8921127PubMed |
Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685.
| Cleavage of structural proteins during the assembly of the head of bacteriophage T4.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlsFags7s%3D&md5=6f0c22623faf3f19401c15a9d52476bdCAS | 5432063PubMed |
Lim, K. J., Odukoya, O. A., Ajjan, R. A., Li, T. C., Weetman, A. P., and Cooke, I. D. (1998). Profile of cytokine mRNA expression in peri-implantation human endometrium. Mol. Hum. Reprod. 4, 77–81.
| Profile of cytokine mRNA expression in peri-implantation human endometrium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXhvV2qtLs%3D&md5=8675c484159e6b93d737d4e8eea30636CAS | 9510015PubMed |
Lim, K. J., Odukoya, O. A., Ajjan, R. A., Li, T. C., Weetman, A. P., and Cooke, I. D. (2000). The role of T-helper cytokines in human reproduction. Fertil. Steril. 73, 136–142.
| The role of T-helper cytokines in human reproduction.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3c%2Fps1aruw%3D%3D&md5=12f352b45c9cef034065fd1972a2849aCAS | 10632428PubMed |
Lindsay, L. A., and Murphy, C. R. (2004). Redistribution of aquaporins in uterine epithelial cells at the time of implantation in the rat. Acta Histochem. 106, 299–307.
| Redistribution of aquaporins in uterine epithelial cells at the time of implantation in the rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtValu7%2FP&md5=c6f88de4d4cde8e09ed18ca5c0089f3aCAS |
Lindsay, L. A., and Murphy, C. R. (2006). Redistribution of aquaporins 1 and 5 in the rat uterus is dependent on progesterone: a study with light and electron microscopy. Reproduction 131, 369–378.
| Redistribution of aquaporins 1 and 5 in the rat uterus is dependent on progesterone: a study with light and electron microscopy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XisFalsb0%3D&md5=44635bfaa13dfd4b18fcf5ae1f5b4ac2CAS | 16452730PubMed |
Makkar, G., Ng, E. H., Yeung, W. S., and Ho, P. C. (2006). Reduced expression of interleukin-11 and interleukin-6 in the periimplantation endometrium of excessive ovarian responders during in vitro fertilization treatment. J. Clin. Endocrinol. Metab. 91, 3181–3188.
| Reduced expression of interleukin-11 and interleukin-6 in the periimplantation endometrium of excessive ovarian responders during in vitro fertilization treatment.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XosFGht7g%3D&md5=696c8facf081ca4d461ba3e7b74d30f0CAS | 16705074PubMed |
Makkar, G., Ng, E. H., Yeung, W. S., and Ho, P. C. (2009). Excessive ovarian response is associated with increased expression of interleukin-2 in the periimplantation endometrium. Fertil. Steril. 91, 1145–1151.
| Excessive ovarian response is associated with increased expression of interleukin-2 in the periimplantation endometrium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXnslWnu7o%3D&md5=4b582142e92ca5f7b2c50f36f0e1c55bCAS | 18331736PubMed |
Matthews, C. J., McEwan, G. T., Redfern, C. P., Thomas, E. J., and Hirst, B. H. (1998). Absorptive apical amiloride-sensitive Na+ conductance in human endometrial epithelium. J. Physiol. 513, 443–452.
| Absorptive apical amiloride-sensitive Na+ conductance in human endometrial epithelium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhtFehsQ%3D%3D&md5=7edeac6f62d07d96084717ab1bc32745CAS | 9806994PubMed |
Nicholson, M. D., Lindsay, L. A., and Murphy, C. R. (2010). Ovarian hormones control the changing expression of claudins and occludin in rat uterine epithelial cells during early pregnancy. Acta Histochem. 112, 42–52.
| Ovarian hormones control the changing expression of claudins and occludin in rat uterine epithelial cells during early pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXksVyksb8%3D&md5=dbc9232fbb5e765495563c14e958bc7cCAS | 19555995PubMed |
Orsi, N. M. (2008). Cytokine networks in the establishment and maintenance of pregnancy. Hum. Fertil. (Camb.) 11, 222–230.
| Cytokine networks in the establishment and maintenance of pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhsFSmt7%2FF&md5=c69ae158b1d7315d8f26588a366da781CAS | 19085258PubMed |
Paulson, R. J., Sauer, M. V., and Lobo, R. A. (1990). Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil. Steril. 53, 870–874.
| 1:STN:280:DyaK3c3js1Sjsw%3D%3D&md5=e2441ff73c30c42534d285a388bc14ceCAS | 2110078PubMed |
Png, F. Y., and Murphy, C. R. (2000). Closure of the uterine lumen and the plasma membrane transformation do not require blastocyst implantation. Eur. J. Morphol. 38, 122–127.
| Closure of the uterine lumen and the plasma membrane transformation do not require blastocyst implantation.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3c7mtVGlsA%3D%3D&md5=94769ef61f418f0559874b1c4dd8abddCAS | 10694909PubMed |
Randall, G. W., Gantt, P. A., Gantt, D., Kirk, M. J., and Romines, N. (1996). Elevated serum progesterone values at the time of ovulation induction in luteal leuprolide acetate-down-regulated GIFT cycles are associated with decreased clinical pregnancy rates. J. Assist. Reprod. Genet. 13, 459–463.
| Elevated serum progesterone values at the time of ovulation induction in luteal leuprolide acetate-down-regulated GIFT cycles are associated with decreased clinical pregnancy rates.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28vjt1Khsg%3D%3D&md5=8c13ac245fa81905b0353118b386751aCAS | 8835672PubMed |
Saito, S., Tsukaguchi, N., Hasegawa, T., Michimata, T., Tsuda, H., and Narita, N. (1999). Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells. Am. J. Reprod. Immunol. 42, 240–245.
| Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3c%2Fks1Gmsw%3D%3D&md5=9b37d20fc66170329c6c62920b92b009CAS |
Salleh, N., Baines, D. L., Naftalin, R. J., and Milligan, S. R. (2005). The hormonal control of uterine luminal fluid secretion and absorption. J. Membr. Biol. 206, 17–28.
| The hormonal control of uterine luminal fluid secretion and absorption.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XntVKnsQ%3D%3D&md5=0a77f83a0bd58e7847ebe1464727f75aCAS | 16440178PubMed |
Schoolcraft, W., Sinton, E., Schlenker, T., Huynh, D., Hamilton, F., and Meldrum, D. R. (1991). Lower pregnancy rate with premature luteinization during pituitary suppression with leuprolide acetate. Fertil. Steril. 55, 563–566.
| 1:STN:280:DyaK3M7mtVOksg%3D%3D&md5=53f172cf85eecca850ccf468433562d3CAS |
Silverberg, K. M., Burns, W. N., Olive, D. L., Riehl, R. M., and Schenken, R. S. (1991). Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins. J. Clin. Endocrinol. Metab. 73, 797–803.
| Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3MzmsFygsQ%3D%3D&md5=4fc0ad2cdb7b9bc5ce9696ca0f1ec628CAS |
Tsang, L. L., Chan, L. N., Wang, X. F., So, S. C., Yuen, J. P., Fiscus, R. R., and Chan, H. C. (2001). Enhanced epithelial Na(+) channel (ENaC) activity in mouse endometrial epithelium by upregulation of gammaENaC subunit. Jpn. J. Physiol. 51, 539–543.
| Enhanced epithelial Na(+) channel (ENaC) activity in mouse endometrial epithelium by upregulation of gammaENaC subunit.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXntlahtrs%3D&md5=4b3abac3c490362a22328be55f04755eCAS | 11564291PubMed |
Van Itallie, C., Rahner, C., and Anderson, J. M. (2001). Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J. Clin. Invest. 107, 1319–1327.
| Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjsl2nt7w%3D&md5=a30785d450ff20128a50befa118d4afdCAS | 11375422PubMed |
von Wolff, M., Thaler, C. J., Strowitzki, T., Broome, J., Stolz, W., and Tabibzadeh, S. (2000). Regulated expression of cytokines in human endometrium throughout the menstrual cycle: dysregulation in habitual abortion. Mol. Hum. Reprod. 6, 627–634.
| Regulated expression of cytokines in human endometrium throughout the menstrual cycle: dysregulation in habitual abortion.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXlvVeqsLo%3D&md5=fc04cc3dbeba66c865c18d41bb9023e8CAS | 10871650PubMed |
Yang, J. Z., Jiang, X., Dong, J., Guo, J., Chen, H., Tsang, L. L., Chung, Y. W., Zhang, X., and Chan, H. C. (2011). Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation. Fertil. Steril. 95, 2100–2106.e2.
| Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXltFymtbw%3D&md5=3186754f8f49f61cd38f9d0c1f62e7d0CAS | 21420082PubMed |