Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Morphometrical study of the effects of ovulation induction drugs in long protocol on ultrastructure of human endometrial epithelium during the implantation Window

Authors
1 Histology Department, Faculty of Medicine, Tabriz Medical Sciences University, Tabriz, Iran
2 Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
3 Anatomy Department, Faculty of Medicine, Tabriz Medical Sciences University, Tabriz, Iran
4 Anatomy Department, Faculty of Medicine, Zahedan Medical Sciences University, Zahedan, Iran
5 Department of Obstet . and Gynecol . of Tabriz University of Medical Science, Tabriz, Iran
6 Department of Statistic, Faculty of Medicine, Boshehr University of Medical Sciences, Bushehr, Iran
Abstract
Introduction: The use of ovulation induction drugs such as: GnRHa, HMG and HCG to induce super ovulation and harvest more oocyte, known as long protocol, is now a commonplace in Assisted Reproductive Techniques (ART). Recent studies and experiences indicate that the rate of successful implantation in stimulatory cycles is less than natural cycles. In the present study we have investigated the possible effects of the above mentioned drugs on ultra structures of human endometrial tissues (luminal and glandular epithelium) on the 20th day of menstrual cycle (LH+6). Materials and Methods: Biopsies were obtained from infertile women who were under super ovulation treatment and from fertile women (as control) who referred to infertility center of Tabriz University of Medical Sciences between 2001- 2003, on day LH+6. The control group (n=5) were normal fertile women who had not received ovulation induction medications and the study group (n=10) were under standard long protocol but the embryo had not been formed due to male factor problem. After preparation and taking light and electron micrographs photographs from samples, qualitative and quantitative evaluations (morphologic and morphometric) were accomplished and the data were compared using unpaired student t test. Results: Qualitative results revealed the presence of nuclear channel system (NCS), vacuoles of glycogen & giant mitochondria in both groups. Quantitative analysis showed that volume fraction of organelles in glandular & luminal endometrial epithelium such as euchromatin to nucleus, RER to cell, mitochondria to cells in test group were significantly higher than those in the control group (P < 0.05) which shows a higher state of activation than those in the controls. Conclusion: These results suggest that ovulation drugs distort the normal development of endome-trium in midluteal phase, coincident with implantation window, and consequently decrease the imp-lantation success rate. Therefore, ART protocols without the use of ovulation induction drugs may improve the successful implantation rate.
Keywords

Dunson D.B., Baird D.D., Colombo B. Increas-ed infertility with age in men and women. Obstet Gynecol.2004;103(1):51-6.
Wilcox A.J., Baird D.D., Weinberg C.R. Time of implantation of the conceptus and loss of preg-nancy. N Engl J Med.1999.10;340(23):1796-9.
Sharkey A.M., Smith S.K. The endometrium as a cause of implantation failure.Best Pract Res Clin Obstet Gynaecol.2003;17(2): 289-307. Review.
Bagchi I.C., Kumar S. Steroid-regulated molec-ular markers of implantation.Semin Reprod Endo- crinol.1999;17(3):235-40 (Review.)
Oehler M.K., Rees M.C., Bicknell R. Steroids and the endometrium.Curr Med Chem.2000;7(5): 543-60 (Review).
Paulson R.J., Sauer M.V., Lobo R.A. Factors affecting embryo implanta‌tion after human invitro fertilization: a hypothesis. Am J Obstet Gynecol. 1990;163:2020-3.
Paulson R.J., Sauer M.V., Lobo R.A. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril.1990;53:870-4.
Check J.H., Nowroozi K., Chase J., Nazari A., Braithwaite C. Comparison of pregnancy rates following in vitro fertilization-embryo transfer between the donors and the recipients in a donor oocyte program. J Assist Reprod Genet.1992;9: 248-50.
Ben-Nun I., Jaffe R., Fejgin M.D., Beyth Y. Therapeutic maturation of endometrium in in vitro fertilization and embryo transfer. Fertil Steril. 1992;57:953-62.
Forman R., Fries N., Testart J., Belaisch-Allan J., Hazout A., Frydman R. Evidence for an adver-se effect of elevated serum estradiol concentra-tions on embryo implantation. Fertil Ateril.1988; 49:118-22.
Simon C., Cano F., Valbuena D., Remohi J., Pellicer A. Clinical evidence for a detrimental effect on uterine receptivity of high estradiol concen‌trations in high and normal responder patients. Hum Reprod.1995;10:2432-7.
Check J.H., Choe J.K., Katsoff D., Summers-Chase D., Wilson C. Con‌trolled ovarian hypersti-mulation adversely impacts implantation follow-ing in vitro fertilization-embryo transfer. J Assist Reprod Genet.1999;16:416-20.
Ng E.H.Y., Yeung W.S.B., Lau E.Y.L., SO W.W.K., Ho P.C. High serum oestradiol concent-rations in fresh IVF cycles do not impair implant-ation and pregnancy rates in subsequent frozenth-awed embryo transfer cases. Hum Reprod.2000; 15:250-5.
Garcia J.E., Acosta A.A., Hsiu J.G., Jones H.W Jr. Advanced endometrial maturation after ovulation induction with human menopausal gonado‌tropin/human chorionic gonadotropin for in vitro fertilization. Fertil Steril.1984;41:31-5.
Levi A.J., Drews M.R., Bergh P.A., Miller B.T., Scott R.T., Jr. Controlled ovarian hypersti-mulation does not adversely affect endometrial receptivity in in vitro fertilization cycles. Fertil Steril.2001;76(4):670-4.
غفاری نوین معرفت، سارانی احمد، صادقی محمدرضا، وارن ام. ای. کشت پولارایز سلول‌های اندومتر و کاربرد آن در مطالعه لانه‌گزینی In vitro. مجله دانشگاه علوم پزشکی و خدمات بهداشتی، درمانی شهید صدوقی یزد، سال 8 (1379)، شمارة 3، صفحات 11-3.
Lenton E.A., Landgren B.M., Sexton L. Nor-mal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase. Br J Obstet Gynaecol.1984;91(7): 685-9.
Li T.C., Rogers A.W., Dockery P., Lenton E. A., Cooke I.D. A new method of histologic dating of human endometrium in the luteal phase. Fertil Steril.1988;50(1):52-60.
Li T.C., Rogers A.W., Lenton E.A., Dockery P., Cooke I. A comparison between two methods of chronological dating of human endometrial biopsies during the luteal phase, and their correla-tion with histologic dating. Fertil Steril.1987;48 (6):928-32.
Dockery P., Rogers A.The effects of steroid on the fine structure of the endimetrium. Baillier-es Clin Obstet Gyncol.1998,3(2):227-247.
Sarani S.A., Ghaffari-Novin M.,Warren M.A., Dockery P., Cooke I.D. Morphological evidence for the ‘Implantation Windows’ in Hum Luminal Endometrium. Human Reprod. 1999;14(12):3101-3106.
Ghaffari Novin M., Sarani S.A., Warren M. A., Cooke I.D. Leukemia Inhibitory Factor in fertile and infertile human reproductive tract in vivo. Iranian J Allergy, Asthma Immun.2000;1 (1):21-27.
Cavagna M., Mantese J.C. Biomarkers of endometrial receptivity. a review. Placenta.2003; 24 Suppl B:S39-47.
Dockery P., Pritchard K., Taylor A., Li T.C., Warren M.A., Cooke I.D. The fine structure of the human endometrial glandular epithelium in cases of unexplained infertility: a morphometric study. Hum Reprod.1993;8(5):667-73.
Nikolettos N., Asimakopoulos B., Vakalopou-los I., Simopoulou M. Endometrial fluid accumul-ation during controlled ovarian stimulation for ICSI treatment. A report of three cases. Clin Exp Obstet Gynecol.2002;29(4):290-2.
Marci R., Senn A., Dessole S., Chanson A., Loumaye E., De Grandi P., Germond M. A low- dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins. Fertil Steril. 2001;75(6):1131-5.
Nikas G., Makrigiannakis A. Endometrial pin-opodes and uterine receptivity.Ann N Y Acad Sci. 2003;997:120-3.
Tavaniotou A., Smitz J., Bourgain C., Devro-ey P. Ovulation induction disrupts luteal phase function. Ann N Y Acad Sci.2001;943:55-63. (Review.)
Klip H., Burger C.W., Kene mans P., Van Leeuwen F.E. Cancer risk associated with subfer- tility and ovulation induction:a review. Cancer Causes Control.2000;11(4):319-44(Review).
Norman R.J., Payne D., Matthews C.D. Preg-nancy following intracytoplasmic sperm injection (ICSI) of a single oocyte in a natural cycle. Hum Reprod.1995;10(7):1626-7.
O' Neill C., Ferrier A.J., Vaughan J., Sinosich M.J. Saunders D.M. Causes of implantation failu-re after in-vitro fertilisation and embryo transfer. Lancet.1985;2:615.
Gidley-Baird A.A., O'Neill C., Sinosich M.J., Porter R.N., Pike I.L., Saun­ders D.M. Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice. Fertil Steril.1986;45:69-74.