By: Myrta Isabel Olivera-Dubón, MD
Director’s Note: As we conclude National Men’s Health Month, we are featuring a 2020 study [1] published in the Journal of International Medical Research and summarized by Myrta Olivera-Dubón, a former FACTS elective participant. Although sildenafil citrate is conventionally used to treat male erectile dysfunction, the study by Li et al explores potential applications of sildenafil citrate to treat female infertility. Given its ability to improve uterine blood flow, sildenafil may prove to be an inexpensive but effective treatment option among women with a thin endometrium. Women struggling with infertility may also benefit from charting with a fertility awareness-based method (FABM), a cost-effective means of gaining insight into the female cycle and addressing issues related to infertility.
Introduction
In the United States, around 19% of women of reproductive age cannot get pregnant after one year of trying to conceive.[2] For this reason, many women resort to different treatments to achieve pregnancy. One of the options in the management of infertility is assisted reproductive technology (ART). Each year, nearly 2% of all infants born in the United States are conceived using ART,[3] which includes in vitro fertilization (IVF), intrauterine insemination (IUI), and other fertility treatments to produce an embryo.
Successful implantation of the embryo requires embryo competency, endometrial receptivity, and synchronized development of the embryo and endometrium.[1] Endometrial receptivity is the ability of the endometrium to successfully attach the blastocyst, nourish it, and maintain its viability for a successful pregnancy.[4] An endometrium of less than 7mm on the day of ovulation is considered thin and represents an adverse prognostic factor for pregnancy.[1]
“An endometrium of less than 7mm on the day of ovulation is considered thin and represents an adverse prognostic factor for pregnancy.”
Sildenafil citrate is used widely to treat male erectile dysfunction. In women, this medication has been found to improve uterine blood flow, leading to an estrogen-induced proliferation of the endometrium. In the 2020 study summarized below, Li et al review the efficacy of sildenafil citrate to treat women with infertility and a thin endometrium.[1]
Methodology
Randomized controlled trials that studied sildenafil citrate versus controls were searched from PubMed, EMBASE, and the Cochrane Controlled Trials Register Database. For the meta-analysis, the inclusion criteria included: (1) women with infertility undergoing in vitro fertilization-embryo transfer, intracytoplasmic sperm injection, frozen-thawed embryo transfer, or induction of ovulation and (2) patients with thin endometrium or poor endometrial response. For the intervention, sildenafil citrate was compared with either no treatment or placebo.
The study assessed endometrial thickness and pattern via ultrasound, and the uterine radial artery resistance index (RI) was measured as well. Clinical pregnancy rate was determined by ultrasonographic documentation of at least one fetus with a heartbeat at 6-7 weeks of gestation. Biochemical pregnancy was identified by a serum hCG level above 10 mIU/mL.
Results
Nine studies with a total of 1,452 patients were used in this meta-analysis. Endometrial thickness was assessed in eight trials with a total of 1,382 participants. The heterogeneity or variation between studies was substantial; therefore, one study was excluded, and the variation significantly diminished. With the final seven pooled analyses, the endometrial thickness in the sildenafil citrate treatment group was significantly higher than in the control group. Changes in the radial artery resistance index (RI) following sildenafil citrate were examined in three studies with a total of 962 participants included. The RI was found to be significantly lower in the sildenafil citrate treatment group than in the control group.
“The endometrial thickness in the sildenafil citrate treatment group was significantly higher than in the control group.”
The clinical pregnancy rate was examined in four studies with a total of 1,110 participants, and the biochemical pregnancy rate was examined in five studies with 400 participants. Both the clinical pregnancy rate and the biochemical pregnancy rate were found to be significantly higher in the sildenafil citrate treatment group than in the control group with no significant heterogeneity. The endometrial pattern was assessed in four studies with a total of 1,130 participants demonstrating a significant proportion of isoechoic endometrium with poorly defined outer walls and central echogenic line in the sildenafil citrate treatment group compared to the control group. Given the moderate heterogeneity found, one study was excluded, resulting in significantly diminished heterogeneity.
Discussion
This research found that women with infertility and a thin endometrium benefit from sildenafil citrate. Optimal endometrial receptivity is important for a successful pregnancy. Thus, this finding suggests a potential therapeutic intervention for women with thin endometrium that is easy to use and inexpensive.
Sildenafil citrate is a phosphodiesterase type 5 inhibitor that enhances the vasodilatory effects of nitric oxide synthase on vascular smooth muscle.[1] Improved uterine blood flow, especially to the basal endometrium, results in estrogen-induced proliferation of the endometrium. Yet, successful implantation also depends on the ability of the blastocyst to penetrate the endometrium and create a source of blood supply.[1] Sildenafil increases the expression of p53 and vascular endothelial growth factor, resulting in improved angiogenesis.[1] Li et al concluded that sildenafil citrate improves endometrial thickness, receptivity, and the clinical pregnancy rate.
“Li et al concluded that sildenafil citrate improves endometrial thickness, receptivity, and the clinical pregnancy rate.”
Compared to the existing literature, this research by Li et al seems more reliable, as it included more studies and followed strict inclusion criteria. Yet, the meta-analysis has some limitations as well, including the fact that some of the studies analyzed differed in timing, dosage, and route of administration of sildenafil citrate. Some studies combined sildenafil citrate with ovulation-stimulating drugs, which could have resulted in bias. Also, some studies lacked follow-up results of miscarriage and live birth rates. Finally, since many studies combined the use of sildenafil with estrogen, more randomized controlled trials are needed that assess the effect of sildenafil citrate on a thin endometrium to further clarify its therapeutic effect.
Director’s Note: Beyond endometrial thickness, many factors may influence a couple’s ability to conceive. When women chart with a fertility awareness-based method, signs or symptoms observed may indicate potential underlying causes of infertility. For example, a chart displaying very short or light periods may reflect the development of a thin uterine lining, which can be confirmed by ultrasound. This research study suggests that physicians may be able to use sildenafil citrate to facilitate the development of the endometrial lining and potentially restore the reproductive system to its normal function.
References
[1] Li, Xin, et al. “Effect of Sildenafil Citrate on Treatment of Infertility in Women with a Thin Endometrium: A Systematic Review and Meta-Analysis.” Journal of International Medical Research, vol. 48, no. 11, 2020, p. 030006052096958., https://doi.org/10.1177/0300060520969584.
[2] Infertility (2023a) Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/reproductivehealth/infertility/index.htm (Accessed: 1 March 2022).
[3] “Art Success Rates.” Centers for Disease Control and Prevention, Centers for Disease Controland Prevention, 14 June 2022, https://www.cdc.gov/art/artdata/index.html.
[4] Heger A, Sator M, Pietrowski D. Endometrial Receptivity and its Predictive Value for IVF/ICSI-Outcome. Geburtshilfe Frauenheilkd. 2012;72(8):710-715. doi:10.1055/s-0032-1315059
ABOUT THE AUTHOR
Myrta Isabel Olivera-Dubón
Myrta Isabel Olivera-Dubón, MD, is a graduate of Universidad Central del Caribe School of Medicine in Bayamón, PR, and will be starting family medicine residency at Glen Cove Hospital in Long Island, NY. She earned a Bachelor of Arts in Psychology and Spanish Literature from George Washington University. Dr. Olivera-Dubón completed the FACTS elective in the fall of 2022 and hopes to integrate fertility awareness-based methods (FABMs) as a tool to educate and empower patients to make choices that are right for them and their families.
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