Sildenafil Citrate and Endometrial Receptivity

Ovulation, conception & implantation oOvulation 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. Implantation o At thisstage 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. “ Infertility a diseaseof the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse Infertility o Global incidenceof 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. Causes of female factorinfertility o Ovulation disorders (40%) o Aging o Diminished ovarian reserve (DOR) o Polycystic ovary syndrome (PCOS) o Premature ovarian failure o Others Thin endometrium o Adequatethickness 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. Thin endometrium o Studiessuggest 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. Understanding the endometrium Endometrium hastwo 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.

• Female-specific studies on sildenafil show mixed results.
• Sildenafil is sometimes used off-label for female libido enhancement.
• Always check for allergies before taking sildenafil citrate tablets.
• Sildenafil may cause vision disturbances in some women.
• Proper hydration can reduce side effects when using sildenafil.
• Combining sildenafil with alcohol can increase risks.
• Be aware of potential interactions with hormonal contraceptives.
• Do not share sildenafil tablets to prevent misuse or overdose.
• Women should report any adverse reactions to their healthcare provider.
• Sildenafil may help with certain conditions like Female Sexual Arousal Disorder.
• Cost of sildenafil for women varies, and insurance may not cover it.
• Follow prescribed instructions precisely to avoid overdose.

Understanding the endometrium o Theaverage 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.

• Sildenafil citrate tablets should be taken with water, not with food.
• Always follow the healthcare provider’s dosage instructions precisely.
• Use sildenafil only under medical supervision if you have health issues.
• Patients should start with lowest effective doses to assess response.
• Report any signs of allergic reactions like rash or swelling immediately.
• Regular check-ups can monitor for any cardiovascular changes.
• Always verify the legitimacy of the medication source.
• Sildenafil may cause hypotension in susceptible women.
• Consider lifestyle modifications to enhance sexual health benefits.
• The drug's effects typically last 4-6 hours.
• Be cautious of counterfeit sildenafil products available online.
• Educate yourself on potential drug interactions before use.

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. Consequence of thin endometrium oIf, due to any cause, this lining becomes thin, it becomes impossible for the fertilized egg to get implanted to the wall.

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Signs and symptoms ofthin 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. Sildenafil ▪Sildenafil is aselective 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) Background The endometrium isthe 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 “ In caseswhere ‘‘thin’’ endometrium results from reduced endometrial blood flow, the use of vasoactive substances may increase endometrial perfusion with a consequent improvement in endometrial growth. Rationale for use ▪Endothelialand 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.

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Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Sildenafil: potential rolein female infertility due to thin endometrium ▪Sildenafil enhances the effect of NO by inhibiting PDE5 which is responsible for degradation of cGMP. ▪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. Indications ▪To improve endometrialthickness in female infertility due to thin endometrium Dose and dosage ▪Thinendometrium: 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. Study 01 ▪Objective tostudy 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 buy sildenafil uk 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. 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.

• Sildenafil citrate can be prescribed off-label for female sexual dysfunction.
• Consult a doctor before using sildenafil citrate tablets for women.
• Side effects in women may include headache, flushing, or nasal congestion.
• Sildenafil works by increasing blood flow to enhance female arousal.
• Dosage for women varies; always follow medical advice.
• Sildenafil tablets may interact with other medications, like nitrates.
• Not approved by FDA specifically for female sexual dysfunction.
• Use with caution in women with heart conditions or high blood pressure.
• Possible benefits include improved libido and vaginal blood flow.
• Sildenafil should be taken on an empty stomach for best results.
• Long-term safety of sildenafil in women is not well established.
• Store sildenafil citrate tablets in a cool, dry place out of children’s reach.

Causes of thin endometriallining Thinning of endometrial lining is a serious problem from gynecological point of view. 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. Signs and symptoms ofthin 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. Sildenafil ▪Sildenafil is aselective 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) Background The endometrium isthe 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 “ In caseswhere ‘‘thin’’ endometrium results from reduced endometrial blood flow, the use of vasoactive substances may increase endometrial perfusion with a consequent improvement in endometrial growth. Rationale for use ▪Endothelialand 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. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF.

How Does Viagra Affect Women?

Sildenafil: potential rolein female infertility due to thin endometrium ▪Sildenafil enhances the effect of NO by inhibiting PDE5 which is responsible for degradation of cGMP. ▪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. Indications ▪To improve endometrialthickness in female infertility due to thin endometrium Dose and dosage ▪Thinendometrium: 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. Study 01 ▪Objective tostudy 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 buy sildenafil uk 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.

What Are the Side Effects in Women?

In group B, 50 patients were given tablet estradiol valerate 2 mg 6-8 hourly. 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 Study 02 ▪Objective: Toevaluate 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.

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Study 02 ▪Results: Of105 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. 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. In group B, 50 patients were given tablet estradiol valerate 2 mg 6-8 hourly. 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 Study 02 ▪Objective: Toevaluate 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. Study 02 ▪Results: Of105 patients, 73 (70%; Group A), attained an endometrial thickness of 9 mm whereas 32 (30%; Group B) did not.

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Ovulation, conception & implantation oOvulation 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. Implantation o At thisstage 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.

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o Implantation of a fertilized ovum is most likely to occur about 9 days after ovulation, ranging between 6 and 12 days. “ Infertility a diseaseof the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse Infertility o Global incidenceof 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. Causes of female factorinfertility o Ovulation disorders (40%) o Aging o Diminished ovarian reserve (DOR) o Polycystic ovary syndrome (PCOS) o Premature ovarian failure o Others Thin endometrium o Adequatethickness 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. Thin endometrium o Studiessuggest 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. 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.

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o Furthermore, thin endometrium causes higher risk of miscarriage Human Fertility 2009;12:198–203. Understanding the endometrium Endometrium hastwo 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. Understanding the endometrium o Theaverage 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.

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Consequence of thin endometrium oIf, 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. Causes of thin endometriallining Thinning of endometrial lining is a serious problem from gynecological point of view. 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. 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. Summary of key findingsof 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).

• Sildenafil citrate tablets are typically taken 30-60 minutes before intimacy.
• Monitoring by a healthcare professional is recommended for women.
• Use sildenafil cautiously if you have a history of stroke or heart attack.
• Combining sildenafil with other ED medications is dangerous.
• Pregnancy and breastfeeding considerations should be discussed with a doctor.
• Sildenafil does not induce arousal but enhances physiological responses.
• Not suitable for women with or at risk of abnormal heart rhythms.
• Potential for psychological as well as physical benefits exists.
• Ensure trusted pharmacy sources when purchasing sildenafil for women.
• Sildenafil is available in various dosages, such as 25 mg, 50 mg, 100 mg.
• Discontinue use if adverse effects like chest pain occur.
• A comprehensive sexual health evaluation can determine if sildenafil is appropriate.

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. Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K.

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Vaginal sildenafil: Role in improving endometrial blood flow in women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Summary of key findingsof 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.

What side effects can this medication cause?

Summary of key findingsof 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. Mishra VV, Choudhary S, Bandwal P, Aggarwal R, Agarwal R, Gandhi K.

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Vaginal sildenafil: Role in improving endometrial blood flow in women undergoing IVF with frozen – Thawed embryo cycles – A study over three cycles. Summary of key findingsof 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. Summary of key findingsof 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. Summary of key findingsof 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.