Luteal supplementation of sildenafil citrate (oral or vaginal) and oral estradiol valerate can be used for improving the EM, therefore can be used as an adjuvant therapy in patients with thin endometrium.
Women with intractable damage to the basal endometrium may be less likely to respond to increased uterine blood flow. Response to sildenafil is also predicated on an adequate serum estrogen level. The adverse effects of oral sildenafil citrate reported in a trial were, mild to moderate in nature and dose related, included headache, flushing, blurring of vision, nausea, and dyspepsia. [25] Another study showed that vaginal sildenafil suppositories are free from side effects related to oral sildenafil. [26] It has been claimed that on their ongoing 3-year experience, the administration of vaginal sildenafil has been totally free of clinical side effects. Sildenafil when compared to estradiol valerate has a better outcome in terms of uterine receptivity, endometrial vascularity, and marginally increased pregnancy outcome in patients undergoing IUI or IVF-ET.
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Furthermore, participants tolerated well vaginal sildenafil with minimal adverse effects.
Hence, here is an attempt to review the effect of sildenafil on the EM, which increases the pregnancy outcome, i.e. its utility in the management of female infertility. Sildenafil (compound UK-92,480) was synthesized by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett. It was initially studied for use in hypertension and angina pectoris. The Phase I clinical trials conducted in Morriston Hospital in Swansea suggested the drug had little effect on angina, but it could induce marked penile erections.
[16] Following this, Pfizer therefore decided to market it for ED, rather than for angina. The drug was patented in 1996; On March 27, 1998, the Food and Drug Administration approved sildenafil citrate for the treatment of ED. Sildenafil citrate (marketed as Viagra) is manufactured by Pfizer Pharmaceuticals, New York, became the first oral drug available for ED. Nitric oxide causes smooth muscle relaxation by generating intracellular cyclic guanosine monophosphate (cGMP) by stimulating the enzyme guanylate cyclase. cGMP promotes dephosphorylation of myosin light chain kinase, thereby interfering with myosin interaction with actin, leading to smooth muscle relaxation and increase in blood flow.
[19] Sildenafil being a selective PDE5 isoenzyme inhibitor enhances the effect of nitric oxide by inhibiting PDE5, which is responsible for degradation of cGMP [Figure 1]. [20] Nitric oxide synthase isoforms have been identified in the vascular muscles of both human endometrium and myometrium. [21] With the use of sildenafil, cGMP remains elevated, which leads to vascular relaxation and increased blood flow to the endometrium. Clinical trials have shown that sildenafil is not useful in angina pectoris because of its many adverse drug reactions. Adverse effects of sildenafil are mainly related to the vasodilation caused by PDE-5 enzyme inhibition. Future studies to evaluate the sildenafil effect on fetal outcome in pregnant women and large sample size clinical trials are needed.
Implantation; sildenafil citrate; thin endometrium; uterine receptivity Pronunciation: sil-DEN-a-fil Generic name: sildenafil Brand names: Revatio, Viagra, Vybrique Dosage form: tablets (20 mg; 25 mg, 50 mg, 100 mg), injection (10 mg/12.5 mL), oral suspension (10 mg/mL), oral film (25 mg, 50 mg, 75 mg, 100 mg) Drug classes: Agents for pulmonary hypertension, Impotence medications Sildenafil is used to treat erectile dysfunction (ED) in adult men or pulmonary arterial hypertension (PAH) in adults and children, depending on the brand or formulation.
Sildenafil tablets (25 mg, 50 mg, 100 mg; Viagra, generic) and sildenafil oral film (25 mg, 50 mg, 75 mg, 100 mg; Vybrique) are used for ED.
| Dosage (mg) | Recommended Usage | Max Daily Dose | Notes |
|---|---|---|---|
| 25 | As prescribed by a doctor | 50 | Starting dose |
| 50 | For increased effect | 100 | Under supervision |
| 100 | Rarely prescribed | N/A | High dose risks |
Sildenafil tablets (20 mg; Revatio, generic), sildenafil oral suspension (Revatio, generic), and sildenafil injection (Revatio, generic) are used for PAH.
Doppler studies revealed a decreased pulsatility index with sildenafil use, and in 3 of the 4 women, a significantly thicker endometrium was achieved with the addition of sildenafil. In a recent comparative prospective study,[23] they compared the effect of vaginal sildenafil citrate and estradiol valerate on EM, blood flow, and pregnancy rates in primary or secondary infertility women undergoing intrauterine insemination (IUI). Patients were evaluated by transvaginal sonography on day 13th of cycle for EM and pattern with number and size of Graafian follicle. Sildenafil significantly increased the endometrial blood flow in comparison to estradiol valerate. The EM and trilaminar pattern of endometrium were comparable in both groups.
Sildenafil marginally increased pregnancy outcome in patients undergoing IUI. Sildenafil acts as a specific PDE-5 inhibitor, hence augments the vasodilatory effects of nitric oxide by preventing the degradation of cGMP, which leads to increase uterine blood flow and thicker endometrium. [7] Alternatively, another study suggested that sildenafil may have an effect on vasoactive cytokines that regulate endometrial development or implantation. They found that sildenafil increases uterine receptivity by the development of spiral arteries and increasing uterine arterial blood flow. [21] They recommended the routine use of oral sildenafil citrate in patients with a previous failure of assisted reproduction technology cycles due to poor EM.
Two small cohort studies denoted that the use of vaginal sildenafil improved uterine artery blood flow and sonographic sildenafil 60mg endometrial appearance. [2629] Sildenafil was reported to augment baseline and estrogen-induced uterine blood flow in surgically menopausal ovine model. [30] Another effect of sildenafil has been described in women with recurrent miscarriages; it has shown to reduce natural killer cell activity in addition to the endometrial growth facilitating effect. [27] VEGF, produced by the epithelial cells, contributes to angiogenesis and increased vascular permeability in the mid-secretory phase, which is necessary for successful implantation, VEGF expression is highest in the mid-secretory phase. A study showed the VEGF protein expression analyzed by Western blotting was significantly lower in the thin endometrium group than that in the normal-thickness endometrium group. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor, which breaks down cyclic GMP and enhances nitric oxide (NO) -mediated smooth muscle relaxation.
[2] Therefore, low VEGF levels in the thin endometrium due to impaired epithelial layer leads to implantation failure and poor endometrial receptivity. Sildenafil citrate stimulated the angiogenic responses of VEGF. A study failed to demonstrate the beneficial effect of sildenafil on thin endometrium, has been reported in women treated with estrogen and sildenafil citrate. Neither vaginal estrogen nor sildenafil significantly improved EM or blood flow in the subsequent frozen embryo transfer (ET) cycle. [33] Thus, the use of sildenafil cannot be expected to help all patients with a thin endometrial lining. In erectile dysfunction (ED), this increases blood flow to penile tissue, facilitating an erection. In pulmonary arterial hypertension (PAH), it dilates pulmonary vessels by the same mechanism, reducing pulmonary blood pressure and improving exercise capacity.
Sildenafil first gained FDA approval on March 27, 1998.
Do not take sildenafil if you are also using a nitrate drug for chest pain or heart problems, including nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and some recreational drugs such as "poppers".
[22] It causes headache, nasal congestion, dizziness, facial flushing, hypotension, and loose motions. Few cases of sudden loss of vision due to nonarteritic ischemic optic neuropathy are recorded. Sildenafil potentiates the vasodilation effect of nitrates, results in fall in BP and myocardial infarction. Therefore, it is contraindicated in patients of coronary heart disease, and caution is advised in the presence of liver or kidney disease, peptic ulcer, and bleeding disorders. It can predispose to priapism in patients with leukemia, sickle cell anemia, and myeloma.
A search was conducted using PUBMED, SCOPUS, and COCHRANE database and focused on peer-reviewed, randomized controlled trials, and observational studies using the keywords: "Sildenafil," "endometrium," "endometrial thickness," "implantation," and "In vitro fertilization" [represented in [Figure 2]. We mainly focused on the effect of sildenafil on EM. All references were scanned from identified articles for additional relevant information. After all the data had been extracted, a table was constructed with respect to first author, study design, patient settings, study groups, outcomes, and conclusion [Table 1]. In one observational study, administration of vaginal sildenafil for 5 weeks improved EM in women with a history of recurrent miscarriage.
[27] Many observational groups also found that administration of vaginal sildenafil up to 10 days improved EM in 70% of the women with at least two consecutive prior in vitro fertilization (IVF) failures attributed to inadequate endometrial development. Among them, implantation and ongoing pregnancy rates were 29% and 45%, respectively. In another study, vaginal sildenafil as well as oral estrogen was administered only in a luteal phase up to 11 days. Sildenafil was administered vaginally at a dosage of 25 mg, once a day, showed beneficial impact on the uterine receptivity. [25] Sher and Fisch evaluated the effect of sildenafil vaginal suppository, on endometrial development in 4 women who had a history of failed 3 artificial reproductive techniques cycles with good ovarian stimulation and thin endometrium (<8 mm). Taking sildenafil with a nitrate medicine can cause a sudden and serious decrease in blood pressure.
| Brand/Generic | Price Range ($) | Details |
|---|---|---|
| Generic Sildenafil | 10-20 per 30 tablets | Most affordable |
| Brand Name (e.g., Viagra) | 50-80 per 30 tablets | Brand premium factors |
| Online Pharmacies | Varies | Sometimes lower prices, ensure legality |
| Insurance Coverage | Limited or none | Depends on country and policy |
Some medicines can cause unwanted or dangerous effects when used with sildenafil.
| Aspect | Approved Use | Off-Label Use |
|---|---|---|
| Indication | Erectile dysfunction (men) | Female sexual arousal disorder |
| Regulatory Approval | Yes in some countries | No or limited approval |
| Common Practice | No | Yes, under medical supervision |
| Risks | Low when prescribed correctly | Unpredictable effects and risks |