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Sildenafil in female infertility (thin endometrium)

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A look into the management of female infertility due to thin endometrium and the role of sildenafil

Veröffentlicht in: Gesundheit & Medizin
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Sildenafil in female infertility (thin endometrium)

  1. 1. SILDENAFIL IN FEMALE INFERTILITY
  2. 2. Contents o Overview of female reproductive system o Infertility o Thin endometrium o Sildenafil o Indications, dose and dosage o Clinical studies o Summary and conclusion
  3. 3. Female reproductive system ▪The female reproductive system is made up of the internal and external sex organs that function in human reproduction. ▪The internal sex organs are the uterus and Fallopian tubes, and the ovaries. ▪The external sex organs are also known as the genitals and these are the organs of the vulva including the labia, clitoris and vaginal opening.
  4. 4. Female internal sex organs Uterus o The uterus is a hollow, muscular, pear-shaped organ. o Connected to the two fallopian tubes on its superior end and to the vagina (via the cervix) on its inferior end. o The inner lining of the uterus, known as the endometrium, provides support to the embryo during early development. o The visceral muscles of the uterus contract during childbirth to push the fetus through the birth canal.
  5. 5. Female internal sex organs Fallopian tubes o The fallopian tubes are a pair of muscular tubes that extend from the left and right superior corners of the uterus to the edge of the ovaries. o The fallopian tubes end in a funnel-shaped structure called the infundibulum, which is covered with small finger-like projections called fimbriae. o The fimbriae pick up released ova from ovary and carry them into the infundibulum for transport to the uterus. o The inside of each fallopian tube is covered in cilia that work with the smooth muscle of the tube to carry the ovum to the uterus.
  6. 6. Female internal sex organs Ovaries o The ovaries are small, paired organs located near the lateral walls of the pelvic cavity. o These organs are responsible for the production of the egg cells (ova) and the secretion of hormones. o The process by which the egg cell (ovum) is released is called ovulation. o The speed of ovulation is periodic and impacts directly to the length of a menstrual cycle.
  7. 7. Ovulation, conception & implantation o Ovulation is the release of egg from the ovaries. o Conception/ Fertilization is the union of a human egg and sperm, usually occurring in the ampulla of the fallopian tube. o Implantation is the very early stage of pregnancy at which the conceptus (fertilized embryo) adheres to the wall of the uterus.
  8. 8. Ovulation, conception & implantation
  9. 9. Implantation o At this stage of prenatal development, the conceptus is a blastocyst. o It is by this adhesion that the fetus receives oxygen and nutrients from the mother to be able to grow. o Implantation of a fertilized ovum is most likely to occur about 9 days after ovulation, ranging between 6 and 12 days.
  10. 10. “ Infertility a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse
  11. 11. Infertility o Global incidence of infertility is about 13- 18% o The incidence of infertility steadily increases in women after age 30. o In India, although population growth is a major concern, there are a substantial number of infertile couples.
  12. 12. Causes of female factor infertility o Ovulation disorders (40%) o Aging o Diminished ovarian reserve (DOR) o Polycystic ovary syndrome (PCOS) o Premature ovarian failure o Others
  13. 13. Thin endometrium
  14. 14. Thin endometrium o Adequate thickness of the endometrium is essential to accomplish a successful pregnancy in ART cycles o ‘‘Thin endometrium” defined as an endometrium thickness that can’t reach the threshold for embryo implantation. Fertil Steril 2008; 89: 832–9.
  15. 15. Thin endometrium o Studies suggest minimal endometrial thickness of 7 mm, (and preferably > 9 mm) to maximize pregnancy rates o Several reports have shown correlation between a ‘‘thin endometrium’’ and low implantation rates o Clinical pregnancy rates increased gradually from 53% among patients with a lining <9 mm, to 77% among patients with a lining of >16 mm. o Furthermore, thin endometrium causes higher risk of miscarriage Human Fertility 2009;12:198–203. J Assist Reprod Genet 1993;10: 215–19. Hum Reprod 1994;9: 363–5. Fertil Steril 2007;87:53–9.
  16. 16. Understanding the endometrium Endometrium has two layers: o a basalis layer that is adherent to the myometrium o and a functional layer which undergoes different phases during a menstrual cycle o This lining is under the control of estrogen hormone and passes through different phases during the monthly menstrual cycle of female.
  17. 17. Understanding the endometrium o The average thickness of endometrium is 8 mm which increases further in pregnancy. Less than 8 mm is considered inadequate o During pregnancy, at least 9 mm of thickness is required to provide a site for proper implantation of fetus. o This thickness not only plays a vital role in the implantation of fetus to the walls of the uterus but also supports the growing baby in the later stages of pregnancy.
  18. 18. Consequence of thin endometrium o If, due to any cause, this lining becomes thin, it becomes impossible for the fertilized egg to get implanted to the wall. o This can lead to infertility of a female uterus and pregnancy cannot take place because a fertilized egg needs a strong support for implantation and support for growing into an embryo.
  19. 19. Causes of thin endometrial lining Thinning of endometrial lining is a serious problem from gynecological point of view. Certain causes are described below. 1. Low estrogen 2. Inadequate blood flow 3. Poor health of endometrial tissue (Any injury, surgery, trauma or infection can cause damage to the endometrial lining) 4. Long term use of birth control pills 5. Excessive use of clomefine citrate
  20. 20. Signs and symptoms of thin endometrial lining There are no specific signs and symptoms related to the thin endometrial lining. However females suffering from thin endometrial lining may present with: 1. Infertility problems 2. Abnormal menstrual cycle 3. Menses accompanied by pain 4. Irregular menses timing 5. Shorter menstrual bleeding
  21. 21. Treatment of thin endometrium
  22. 22. Sildenafil ▪Sildenafil is a selective inhibitor of Phosphodiesterase -5 (PDE-5), which is cGMP- specific and responsible for the degradation of cGMP ▪Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5)
  23. 23. Background The endometrium is the special epithelial lining of the uterine cavity It has two layers: A superficial functional layer and a deeper basal layer The endometrial growth is reliant on the uterine blood flow Uterine blood flow is closely related with the vascular development of endometrium plays a significant role in the development of a dominant follicle, formation of a corpus luteum, and growth of endometrium This is essential to support endometrial growth after menstruation and to provide a vascularized receptive endometrium for implantation
  24. 24. “ In cases where ‘‘thin’’ endometrium results from reduced endometrial blood flow, the use of vasoactive substances may increase endometrial perfusion with a consequent improvement in endometrial growth. Improving endometrial perfusion
  25. 25. Rationale for use ▪Endothelial and inducible NO synthase isoforms have been identified in both the vascular endothelium of human endometrium and in the myometrium ▪Vaginally administered sildenafil suppositories could lead to an improvement in uterine blood flow and, in conjunction with controlled ovarian hyperstimulation, lead to estrogen-induced proliferation of the endometrial lining Telfer JF, Irvine GA, Kohnen G, Cambell S, Cameron IT. Expression of endothelial and inducible nitric oxide synthase in non-pregnant and decidualized human endometrium. Mol Hum Reprod 1997;3:69–75. Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod 2000;15:806–9.
  26. 26. Sildenafil: potential role in female infertility due to thin endometrium ▪Sildenafil enhances the effect of NO by inhibiting PDE5 which is responsible for degradation of cGMP. ▪Sildenafil is a selective inhibitor of the type-V cGMP- specific phosphodiesterase. ▪With the use of sildenafil, cGMP levels remain elevated, which leads to vascular relaxation and increased blood flow to improved the endometrial thickness Sher G and Fisch JD. Vaginal sildenafil (Viagra): A preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum . Reprod. 2000; 15: P806-809.
  27. 27. Indications ▪To improve endometrial thickness in female infertility due to thin endometrium
  28. 28. Dose and dosage ▪Thin endometrium: Sildenafil citrate 25 mg vaginally every 6 hours from day 8th of the cycle for 5 days (3-10 days) ▪In ART: Vaginal sildenafil citrate suppositories (25 mg) four times per day from the third day of the stimulation protocol to the evening before oocyte retrieval.
  29. 29. Clinical studies
  30. 30. Study 01
  31. 31. Study 01 ▪Objective  to study and compare the effect of vaginal sildenafil citrate and estradiol valerate on endometrial thickness, blood flow and pregnancy rates in infertile women undergoing intrauterine insemination ▪Methodology  Comparative prospective study including 100 women with primary or secondary infertility with stimulated cycles undergoing IUI  In group A, 50 patients were included and given sildenafil citrate 25 mg vaginally every 6 hours from day 8th of the cycle.  In group B, 50 patients were given tablet estradiol valerate 2 mg 6-8 hourly.
  32. 32. Study 01 ▪Results  64% patients given sildenafil vaginally had vascularity up to zone 3 whereas 48% patients given estradiol valerate orally had zone 3 endometrial vascularity (p value = 0.038)  The clinical pregnancy rates were 10 (20%) in group 1 and 7 (14%) in group 2 after 3 cycles of IUI. (p value = 0.042) ▪Conclusion  Sildenafil when compared to estradiol valerate has better results as far as endometrial vascularity is concerned  and marginally increased pregnancy outcome in patients undergoing IUI
  33. 33. Study 02
  34. 34. Study 02 ▪Objective:  To evaluate the effects of vaginally administered sildenafil on endometrial thickness and IVF outcome in a large cohort of infertile women with poor endometrial development. ▪Intervention:  Patients underwent IVF using a long GnRH-a protocol with the addition of sildenafil vaginal suppositories (25 mg, 4 times per day) for 3–10 days. ▪Main Outcome Measures:  Peak endometrial development, pregnancy, and implantation rates.
  35. 35. Study 02 ▪Results:  Of 105 patients, 73 (70%; Group A), attained an endometrial thickness of 9 mm  whereas 32 (30%; Group B) did not.  Implantation and ongoing pregnancy rates were significantly higher for Group A (29% and 45%) than for Group B (2% and 0). ▪Conclusion:  Vaginal administration of sildenafil enhanced endometrial development in 70% of patients studied.  High implantation and ongoing pregnancy rates were achieved in a cohort with a poor prognosis for success.
  36. 36. Study 03 ▪Study details:  In a prospective study, 10 patients in our fertility center gave their informed consent to be treated with vaginal sildenafil citrate suppositories (25 mg) four times per day from the third day of the stimulation protocol to the evening before oocyte retrieval.
  37. 37. Study 03
  38. 38. Summary of key findings of other supporting studies  Sildenafil improved endometrial vascularity and marginally increased pregnancy outcome. The clinical pregnancy rates were 20% in SC group and 14% in estrogen group after 3 cycles of IUI (P=0.042)  The endometrial vascularity was significantly higher after sildenafil treatment in 21 patients (P<0.01). Embryo transfer was done in 19 women, out of which 9 (47.36%) women conceived Mangal S, Mehirishi S. To study and compare the effect of vaginal sildenafil and estradiol valerate on endometrial thickness, blood flow and pregnancy rates in infertile women undergoing intrauterine insemination. Int J Reprod Contracept Obstet Gynecol 2016;5:2274-7. Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K. Vaginal sildenafil: Role in improving endometrial blood flow in women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Int J Sci Res 2015;4:292-4. Study04Study05
  39. 39. Summary of key findings of other supporting studies  The clinical pregnancy rate was two-fold higher in the study group (Sildenafil), compared to control group but not statistically significant (47.6% vs. 25.9%, P=0.209)  All three (A: Vit E, B: L-arginine, C: Sildenafil) interventions improved uterine RA-RI and EM in the patients with a thin endometrium  Pregnancy rates: 50% in sildenafil group, 11% in L-arginine, 20% in Vitamin E, and nil in control group Kim KR, Sun Lee H, Ryu HE, Park CY, Min SH, Park C, et al. Efficacy of luteal supplementation of vaginal sildenafil and oral estrogen on pregnancy rate following IVF-ET in women with a history of thin endometria: A pilot study. J Womens Med 2010;3:155-8. Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K. Vaginal sildenafil: Role in improving endometrial blood flow in women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Int J Sci Res 2015;4:292-4. Study06Study07
  40. 40. Summary of key findings of other supporting studies  Long GnRH-Lupron was used for ovarian stimulation  Sildenafil vaginal suppositories 25 mg, 4 times/day for 3–10 days  Sildenafil enhanced endometrial development >9 mm in 70% of patients studied.  It increased the implantation rate and ongoing pregnancy rate in above patients compared to patients with <9 mm endometrial lining Sher G, Fisch JD. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril 2002;78:1073-6. Study08
  41. 41. Summary of key findings of other supporting studies  The NK-cell activity was significantly decreased after vaginal sildenafil therapy endometrial thickness was significantly increased  Sildenafil decreases pulsatility index indicating increase in uterine blood flow and increased endometrial thickness. Jerzak M, Kniotek M, Mrozek J, Górski A, Baranowski W. Sildenafil citrate decreased natural killer cell activity and enhanced chance of successful pregnancy in women with a history of recurrent miscarriage. Fertil Steril 2008;90:1848-53. Sher G, Fisch JD. Vaginal sildenafil (Viagra): A preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod 2000;15:806-9. Study09Study10
  42. 42. Summary & conclusion ▪Luteal supplementation of sildenafil citrate can be used for improving the endometrial thickness, therefore can be used as an adjuvant therapy in patients with thin endometrium. ▪Sildenafil has good outcome in terms of uterine receptivity, endometrial vascularity, and marginally increased pregnancy outcome in patients undergoing IUI or IVF-ET. ▪Vaginal sildenafil is generally well tolerated with minimal adverse effects (vaginal sildenafil suppositories are free from side effects related to oral sildenafil)

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