|Year : 2016 | Volume
| Issue : 2 | Page : 131-136
An overview on sildenafil and female infertility
Jyoti M Benni1, Paragouda A Patil2
1 Department of Pharmacology, KLEU's JN Medical College, Belgaum, Karnataka, India
2 Department of Pharmacology, USM KLE, International Medical Programme, Belgaum, Karnataka, India
|Date of Web Publication||29-Sep-2016|
Jyoti M Benni
Department of Pharmacology, KLEU's JN Medical College, Belgaum - 590 010, Karnataka
Source of Support: None, Conflict of Interest: None
Endometrial thickness (EM) is one of the strongest predictors of implantation rate and ongoing pregnancy success rate. The endometrial growth is dependent on the uterine blood flow and angiogenesis. Recently, some reports discussed the possible beneficial effects of sildenafil citrate on EM. Sildenafil citrate leads to smooth muscle relaxation and vasodilation. Because of these biological properties, it is a potential candidate for female infertility, especially in the management of thin endometrium, which leads to low implantation and pregnancy rates. An updated electronic search was performed through PUBMED, MEDLINE, and COCHRANE and focused on peer-reviewed, randomized controlled trials, and observational cohort or case-control studies for the role of sildenafil in thin endometrium. Systematic search through all the clinical studies showed favorable results. They documented the beneficial role of sildenafil citrate in the treatment of thin endometrium in failed in vitro fertilization-embryo transfer cycles, assisted intrauterine insemination cycles, or resistant endometrium, where it increased the uterine receptivity.
Keywords: Implantation, sildenafil citrate, thin endometrium, uterine receptivity
|How to cite this article:|
Benni JM, Patil PA. An overview on sildenafil and female infertility. Indian J Health Sci Biomed Res 2016;9:131-6
| Introduction|| |
Successful pregnancy requires adequate growth of the endometrium to support the ovum implantation during menstrual cycle. Endometrial thickness (EM) is one of the strongest predictors of implantation. The pregnancy rates are higher when the endometrium thickness is >9 mm  and endometrial lining <7 mm had low pregnancy rates because of poor support for implantation. 
The endometrium is the special epithelial lining of the uterine cavity above the level of internal os. It has two layers: A superficial functional layer and a deeper basal layer. The endometrial growth is reliant on the uterine blood flow and angiogenesis.  Uterine blood flow is closely related with the vascular development of endometrium. Basal one-third layer is supplied by small, straight, and short arteries and superficial two-third of endometrium is supplied by coiled arteries, branch of uterine artery.  The average EM is about 8-10 mm in the secretory phase. Angiogenesis plays a significant role in the development of a dominant follicle, formation of a corpus luteum, and growth of endometrium.  Angiogenesis is essential to support endometrial growth after menstruation and to provide a vascularized receptive endometrium for implantation. 
Endometrial growth is regulated by the hormones (estrogen and progesterone) and growth factors such as vascular endothelial growth factor (VEGF).  Some of these factors are produced locally and act via paracrine mechanisms; others have to be transferred to the endometrium. Sufficient uterine blood supply is required for these factors to reach the endometrium, especially to its functional layer.  Estrogen-induced endometrial proliferation after menstruation is mainly dependent on blood flow to the basal endometrium.  Estrogen regulates the proliferative phase and estrogen-primed endometrium produces progesterone receptors, which are necessary for the secretory phase endometrial growth regulated by progesterone. 
Thin endometrium can be due to various reasons, mainly surgical procedures such as cervical dilation and curettage (D and C), radiotherapy, recurrent infections, congenital Müllerian anomalies, and use of clomiphene citrate.  The D and C leads to intrauterine adhesions (IUAs), and the Asherman syndrome is a severe degree of IUA. Patients who receive radiotherapy below the diaphragm are more vulnerable. Radiotherapy can lead to disruption of uterine blood vasculature and reduced uterine size. Chronic endometritis reduced endometrial receptivity and altered uterine contractility leading to infertility.  It can be due to various reasons such as infections due to tuberculosis or chlamydia or intrauterine devices. Clomiphene citrate used for ovulation induction can lead to thin endometrium because of its luteal phase defect (antiestrogenic effect on endometrium), which reduces the chances of implantation. A previous study has reported that a thin endometrium is characterized by high blood flow impedance of uterine radial artery, poor epithelial growth, decreased expression of VEGF, and poor vascular development. 
Hence, adjuvant medications causing vasodilation have been suggested to be beneficial in women with thin endometrium. Several agents such as antithrombotic agents, aspirin,  and heparin have been evaluated by several groups. Heparin was found to improve pregnancy rates among women with thrombophilia and recurrent abortions.  Others included L-arginine, Vitamin E, nitrates, sildenafil, estrogen, pentoxifylline, tocopherol, and intrauterine infusion of growth factor such as Granulocyte-colony stimulating factor. , Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor is now one of the standard treatments for erectile dysfunction (ED) since decades.  Beyond its urological scope, new therapeutic applications are being explored because of its vasodilatory property. 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.
| Pharmacology of Sildenafil|| |
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.  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. 
IUPAC name: 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine citrate. 
Chemical formula - C 22 H 30 N 6 O 4 S.
| Mechanism of Action|| |
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.  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].  Nitric oxide synthase isoforms have been identified in the vascular muscles of both human endometrium and myometrium.  With the use of sildenafil, cGMP remains elevated, which leads to vascular relaxation and increased blood flow to the endometrium.
|Figure 1: Schematic diagram illustrating the mechanism of action of the sildenafil citrate|
Click here to view
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.  It causes headache, nasal congestion, dizziness, facial flushing, hypotension, and loose motions. Gastritis and dyspepsia can occur due to lower esophageal sphincter relaxation. 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. 
| Literature Search - Role of Sildenafil in Endometrial Thickness|| |
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].
|Table 1: Studies supporting the role of sildenafil citrate in patients with thin endometrium|
Click here to view
| Discussion|| |
In one observational study, administration of vaginal sildenafil for 5 weeks improved EM in women with a history of recurrent miscarriage.  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.  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). 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. All three of these women conceived. 
In a recent comparative prospective study,  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 13 th 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. 
| Mechanism of Action of Sildenafil on Endometrium|| |
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.  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.  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 endometrial appearance. , Sildenafil was reported to augment baseline and estrogen-induced uterine blood flow in surgically menopausal ovine model.  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.  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.  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. EM was compared between the groups. Neither vaginal estrogen nor sildenafil significantly improved EM or blood flow in the subsequent frozen embryo transfer (ET) cycle.  Thus, the use of sildenafil cannot be expected to help all patients with a thin endometrial lining. 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.  Few patients reported vaginal irritation.  Another study showed that vaginal sildenafil suppositories are free from side effects related to oral sildenafil.  It has been claimed that on their ongoing 3-year experience, the administration of vaginal sildenafil has been totally free of clinical side effects. 
| Conclusion|| |
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. 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. Furthermore, participants tolerated well vaginal sildenafil with minimal adverse effects. Future studies to evaluate the sildenafil effect on fetal outcome in pregnant women and large sample size clinical trials are needed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial thickness on IVF/ICSI outcome. Hum Reprod 2003;18:2337-41.
Miwa I, Tamura H, Takasaki A, Yamagata Y, Shimamura K, Sugino N. Pathophysiologic features of "thin" endometrium. Fertil Steril 2009;91:998-1004.
Padubidri VG, Daftary SN. Normal Histology. In: Howkins and Bourne ′Shaw′s textbook of gynaecology′. 13 th
ed., Ch. 2. New Delhi: Elsevier publishers; 2004. p. 30-32.
Sugino N, Suzuki T, Sakata A, Miwa I, Asada H, Taketani T, et al
. Angiogenesis in the human corpus luteum: Changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab 2005;90:6141-8.
Smith SK. Angiogenesis and implantation. Hum Reprod 2000;15 Suppl 6:59-66.
Sugino N, Kashida S, Karube-Harada A, Takiguchi S, Kato H. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction 2002;123:379-87.
Fahmy AA, El Sokkary M, Sayed S. The value of oral sildenafil in the treatment of female infertility: A randomized clinical trial. Life Sci J 2015;12:78-82.
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.
Garcia-Velasco JA, Acevedo B, Alvarez C, Alvarez M, Bellver J, Fontes J, et al
. Strategies to manage refractory endometrium: State of the art in 2016. Reprod Biomed Online 2016;32:474-89.
Matteo M, Cicinelli E, Greco P, Massenzio F, Baldini D, Falagario T, et al
. Abnormal pattern of lymphocyte subpopulations in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol 2009;61:322-9.
Hsieh YY, Tsai HD, Chang CC, Lo HY, Chen CL. Low-dose aspirin for infertile women with thin endometrium receiving intrauterine insemination: A prospective, randomized study. J Assist Reprod Genet 2000;17:174-7.
Rubinstein M, Marazzi A, Polak de Fried E. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation and pregnancy rates in patients undergoing in vitro
fertilization: Prospective, randomized, double-blind placebo-controlled assay. Fertil Steril 2000;73:1069-71.
Senturk LM, Erel CT. Thin endometrium in assisted reproductive technology. Curr Opin Obstet Gynecol 2008;20:221-8.
Lebovitz O, Orvieto R. Treating patients with "thin" endometrium - An ongoing challenge. Gynecol Endocrinol 2014;30:409-14.
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996;78:257-61.
Terrett NK, Bell AS, Brown D, Elllis P. Sildenafil (Viagra), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 1996;6:1819-24.
Pubchem - Open Chemistry Database, Sildenafil (Compound Summary). National Center for Biotechnology Information, U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894, USA. Available from: https://www.pubchem.ncbi.nlm.nih.gov/compound/sildenafil. [Last accessed on 2016 Aug 09].
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12.
Jackson G, Montorsi P, Cheitlin MD. Cardiovascular safety of sildenafil citrate (Viagra): An updated perspective. Urology 2006;68 3 Suppl: 47-60.
Dehghani Firouzabadi R, Davar R, Hojjat F, Mahdavi M. Effect of sildenafil citrate on endometrial preparation and outcome of frozen-thawed embryo transfer cycles: A randomized clinical trial. Iran J Reprod Med 2013;11:151-8.
Tripathi KD, editor. Androgens and drugs for erectile dysfunction. In: Text Book of Essentials of Medical Pharmacology. 7 th
ed., Ch. 21. New Delhi: Jaypee Publishers; 2013. p. 303-4.
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.
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.
Takasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino N. Endometrial growth and uterine blood flow: A pilot study for improving endometrial thickness in the patients with a thin endometrium. Fertil Steril 2010;93:1851-8.
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.
Richter KS, Bugge KR, Bromer JG, Levy MJ. Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro
fertilization with transfer of two blastocyst-stage embryos. Fertil Steril 2007;87:53-9.
Zoma WD, Baker RS, Clark KE. Effects of combined use of sildenafil citrate (Viagra) and 17beta-estradiol on ovine coronary and uterine hemodynamics. Am J Obstet Gynecol 2004;190:1291-7.
Di X, Gennings C, Bear HD, Graham LJ, Sheth CM, White KL Jr., et al
. Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat 2010;124:349-60.
Pyriochou A, Zhou Z, Koika V, Petrou C, Cordopatis P, Sessa WC, et al
. The phosphodiesterase 5 inhibitor sildenafil stimulates angiogenesis through a protein kinase G/MAPK pathway. J Cell Physiol 2007;211:197-204.
Check JH, Graziano V, Lee G, Nazari A, Choe JK, Dietterich C. Neither sildenafil nor vaginal estradiol improves endometrial thickness in women with thin endometria after taking oral estradiol in graduating dosages. Clin Exp Obstet Gynecol 2004;31:99-102.
[Figure 1], [Figure 2]
|This article has been cited by|
||Sildenafil Supplementation for Women Undergoing Infertility Treatments: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
| ||Loris Marin,Alessandra Andrisani,Luciana Bordin,Francesco Dessole,Marco Noventa,Amerigo Vitagliano,Giampiero Capobianco,Guido Ambrosini |
| ||Journal of Clinical Medicine. 2021; 10(19): 4346 |
|[Pubmed] | [DOI]|
||TO COMPARE THE COMBINED EFFECT OF ORAL SILDENAFIL AND ESTRADIOL VALERATE TO ESTRADIOL VALERATE ALONE IN PATIENTS WITH CLOMIPHENE INDUCED CYCLES IN INFERTILE WOMEN ON ENDOMETRIAL THICKNESS.
| ||Rekha Rani,Shikha Singh,Sangita Sahu,Ruchika Garg,Urvashi Urvashi,Vandana Sharma |
| ||INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH. 2021; : 13 |
|[Pubmed] | [DOI]|
||A randomized clinical trial of sildenafil plus clomiphene citrate to improve the success rate of ovulation induction in patients with unexplained infertility
| ||Ahmed A. Aboelroose,Zakia M. Ibrahim,Elham H. Madny,Ahmed M. Elmazzahy,Omima T. Taha |
| ||International Journal of Gynecology & Obstetrics. 2020; |
|[Pubmed] | [DOI]|