Stesura Seveso 361Archivio Italiano di Urologia e Andrologia 2021; 93, 3 ORIGINAL PAPER No conflict of interest declared. dicted that 322 million men around the world will have ED by 2025 (2). The increasing prevalence of ED leads to a more significant economic burden. At this point, oral phosphodiesterase-5 inhibitors (PDE5i) are the first choice of treatment for ED because they are safe, efficient, cost- effective and non-invasive (3). PDE5i which were approved by the Food and Drug Administration (FDA) for ED and other diseases are shown on the timeline (4, 5) (Figure 1). Considering sexual disorders, patients may not feel com- fortable to share their problems with the doctors. Then they can try to find out how to treat their sexual problems by themselves on the web (6). A survey from The National Men’s Health Week showed that 44% of men who devel- oped symptoms of ED, would hesitate to look for a treat- ment, and 11% of them would not visit a doctor if they decide they might need a medical treatment like PDE5i (7). Google trends (GT) is one of these search tools which pro- vides worldwide data about the popularity of searched items during a period. Thus, GT has been continuously used more by marketing specialists for gathering informa- tion about potential client interest, as well as differences in that interest by geographic location and time. In the med- ical area, GT has been used to specify patient interest in surgical procedures and medical treatments (8). Therefore, we aimed to analyze the trend change of the most popular PDE5i over time including COVID-19 pan- demic and geography by using GT data. We also aimed to reveal the possible reasons for the trend changes of PDE5i in terms of time and geography. MATERIALS AND METHODS GT produces worldwide search volume info since 2004, offering time-period and category patterns according to a specific term. GT is able to generate a “line-graph”, show- ing how interest has increased or decreased over a period within specific territories. The search values for specific terms are indexed as relative search volume (RSV), which is presented on a scale from 0-100. A value of RSV 100 indicates the highest search trends, while 50 represents half of the searches. However, 0 demonstrates that no suf- ficient data were found for the term. By using the estimated annual RSV (ARSV) annual percentage Objectives: We aimed to analyze the trend change of the most popular Phosphodiesterase-5 Inhibitors (PDE5i) over time and geography by using Google Trends (GT) data in 10 years period and COVID-19 pandemic. Materials and methods: GT is able to generate a “line-graph”, showing how interest has increased or decreased over a period within specific territories. The search values for specific terms are indexed as relative search volume (RSV), which is presented on a scale from 0-100. Avarage annual percentage change (AAPC) and RSV were analyzed to evaluate gain or loss of inter- est in trends. Search terms were generated for Food and Drug Administration (FDA)-approved PDE5i; tadalafil, sildenafil, var- denafil, avanafil, and their most-used brand names. The data was within “worldwide” from 1 January 2010, to 31 December 2020, using the ‘‘global’’ query category. Results: The overall interest in PDE5i has doubled. Sildenafil has become the most trend PDE5i of today with a regular increase (AAPC: 0.016, p < 0.01). Although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised and tadalafil has become the 2nd most popu- lar PDE5i recently (AAPC: 0.007, p < 0.01). For vardenafil there has been a decreased interest (AAPC: -0.009, p < 0.01). There is no significant change in avanafil trend (AAPC: 0.000, p: 0.5). All PDE5i interest on GT decreased notably from February to June 2020. But after June, search trends reached the level before the COVID-19 period in a month. Conclusions: These findings show us, with its increasing preva- lence, erectile dysfunction (ED) has become a major public health problem. People from different geographies search the internet for ED treatment options. Patients should be informed that ED may be the first sign of many comorbid diseases, and patients with ED should be referred to a health institution for diagnosis and treatment. KEY WORDS: Google trends; Erectile dysfunction; Phosphodiesterase type-5 inhibitors; Health behaviors; Real-world evidence. Submitted 28 April 2021; Accepted 14 June 2021 INTRODUCTION Erectile dysfunction (ED) is the recurrent or persistent inability of men to achieve and/or maintain adequate penile erections for satisfactory sexual performance (1). It is pre- Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic Müslim Doğan Değer 1, Serdar Madendere 2 1 Department of Urology, Edirne Sultan 1st Murat State Hospital, Edirne, Turkey; 2 Department of Urology, Gümüşhane State Hospital, Gümüşhane, Turkey. DOI: 10.4081/aiua.2021.3.361 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 3 M. Doğan Değer, S. Madendere 362 change (APC), linear trends in RSV were shown. To measure variations in ARSV between 2 join points, APC was evaluat- ed. Estimated average APC (AAPC) and respective confidence of intervals (CIs) were used to determine linear trends of ARSV during the whole period. AAPC analysis in rate dur- ing a period is provided by a natural log-linear model ([ln(y)=xb]). A negative value of AAPC shows a decreasing RSV and a positive rate refers to increased interest. A log (x+1) transformation was used to the whole dataset if a dependent variable was zero. To assess any inflection points with a significant difference in the trend’s slope, a permuta- tion test was used. When slopes were identified or not the trends were called non-constant or constant, respectively. The Kendall Trend Tau Test was applied to compare data which is collected over time for trends decreasing or increasing consis- tently. Search terms were generated for FDA- approved PDE5i; tadalafil, sildenafil, varde- nafil, avanafil, and their most-used brand names. The data was within “worldwide” from 1 January 2010, to 31 December 2020, using the ‘‘global’’ query category. Data obtained from search terms were plot- ted in polynomial trend lines. Moreover, international trends for each PDE5i indi- vidually were searched and shown in a sep- arate figure. All trend and statistical analy- ses were performed using Microsoft Excel v.16.0 (Redmond, Wash) and SPSS v.24.0 (SPSS Inc., Chicago, IL, USA). RESULTS Trends in geographic locations Interest in sildenafil was mostly high in South America and Europe, interest in vardenafil was highest in the Eastern European and Asian countries. Interest in tadalafil was not superior especially in a specific region. The highest interest in avanafil was in Mediterranean countries (Figure 2) (Table 1). Trends in interest over time The overall interest in PDE5i has doubled in the last 10 years. The leading trend was vardenafil from 2010 to Figure 1. Milestones in the development of phosphodiesterase type 5 inhibitors. Figure 2. International trends in phosphodiesterase- 5 inhibitors.The world map shows the countries with the highest Google Trends search volumes for each search term. The darker regions indicate the places where the search terms are more likely to be searched. If a region on the map isn't highlighted, it doesn't mean the term is not used in that region, however, it is less popular than other regions. 363Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Web searches for erectile dysfunction treatments 2013, but it has been decreasing over time (AAPC: -0.009, p < 0.01). Sildenafil has become the most trend PDE5i of today with a regular increase (AAPC:0.016, p < 0.01). Although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised geometrically like sildenafil, and tadalafil has become the 2nd most popular PDE5i recently (AAPC: 0.007, p < 0.01). Avanafil has not become wide- spread and its trend has shown slight movement in the last 1 year, but it has not been a competitor in general (AAPC: 0.000, p: 0.5) (Figure 3) (Table 2). The global interest in the term "erectile dysfunction" on GT has been substantially lower than the interest in all PDE5i. There was no relationship between the PDE5i interest and the interest in global erectile dysfunction issue. Trends in interest in COVID-19 period All PDE5i interest on Google Trend decreased notably from February to June 2020. But after June, search trends reached the level before the COVID-19 period in a month. Then the increase-decrease routine continued as before (Figure 3). DISCUSSION With the aging population and the increase of comorbid diseases, ED has become more prevalent. Accordingly, the demand for ED treatments is increasing (9, 10). Because PDE5i are both non-invasive and more cost- effective treatments of ED compared to other methods (3, 11), we can see a rising interest in them over the world in the last 10 years in our results. Jena et al. found a strong correlation between web search- es for Human Immunodeficiency Virus (HIV) terms and HIV regional incidence rates in the United States (US) (12). Tijerina et al. found also a correlation between breast sur- gery procedures search terms and annual case volumes of breast procedures performed in the US (13). Similarly, in our study, there was a correlation between the trend rate and the amount of PDE5i sales in Europe (14). We demonstrated that people initially search for treatment options for ED on the web, then they buy the most suit- able one for themselves. On this point, there is a risk that can endanger patients’ health. Countrefeit PDE5i have been an important problem in both well-developed and developing countries. They are cheaper and easy to obtain Table 2. AAPC results of PDE5i queries from 2010 until 2020. PDE5i Lower Upper AAPC Lower Upper Test *p-value endpoint endpoint CI CI statistic Sildenafil 2010 2020 0.016 0.015 0.017 0.874 < 0.01 Vardenafil 2010 2020 -0.009 -0.0010 -0.0010 -0.806 < 0.01 Tadalafil 2010 2020 0.007 0.006 0.008 0.791 < 0.01 Avanafil 2010 2020 0.000 0.000 0.000 0.192 0.5 CI: Confidence interval; AAPC: Avarage annual percentage change; PDE5i: Phosphodiestarese-5 inhibitors. * The Kendall Trend Tau Test was applied to define p value. Table 1. Most trend five countries for each PDE5i. Figure 3. Google Trends relative search volume for phosphodiesterase-5 inhibitors by month, January 2010 to December 2020. Sildenafil Vardenafil Tadalafil Avanafil Finland Japan Brazil Italy Chile Russia Vietnam Portugal Colombia Ukraine France Egypt Argentina Bulgaria India France Peru Israel United Arab Emirates China Archivio Italiano di Urologia e Andrologia 2021; 93, 3 M. Doğan Değer, S. Madendere 364 through the web (15). Considering the side effects of the drugs and their interactions with other drugs, the patient may be harmed. Moreover, clinical examination is neces- sary because ED can be the first symptom of cardiovascu- lar diseases, also multiple risk factors and comorbidities are generally associated with ED (16). Both to prevent the use of counterfeit medicines and ensure the correct use of FDA-approved PDE5i, patients’ awareness should be raised to see a doctor when they have ED. When the trends of PDE5i are interpreted separately, it is seen that sildenafil has a clear superiority in recent years. According to the “CONSER” survey conducted by the Italian Society of Andrology, the speed of action is the most important factor for both physicians and patients when choosing a PDE5i. On this point, a new oro-soluble form of sildenafil offers advantages (17). Comparing the total numbers of PDE5i prescriptions in Europe, sildenafil is superior to tadalafil and vardenafil in the literature similar to our results of search trends (14). Being the first product in the market, brand name recognition, high efficacy and patient satisfaction are the main factors that maintain the popularity of sildenafil. Another important point is the lower cost of sildenafil compared to other PDE5i. Hansen et al. showed that ED treatment with sildenafil was a cost- effective alternative compared to vardenafil and tadalafil (18). Moreover, sildenafil searches seem to be prominent, especially in Latin American countries. Successful results in ED treatment with sildenafil in Latin America may have made sildenafil popular in this region (19). On the other hand, higher prescription rates of tadalafil in a prospective study in Latin America show that trends in the region may change in times advancing (20). Our study shows that the trend of tadalafil has increased significantly and tadalafil has become popular in many countries from different continents recently. This popu- larity in different geographies can be interpreted with the high satisfaction of patients. The long duration of action of tadalafil gives the freedom to have unplanned sexual intercourse. This takes away timing concerns and pro- vides sexual self-confidence, especially for the young men with mild sexual dysfunction (21). No interaction with fatty food is another advantage of tadalafil (22). Other important developments that increased the use of tadalafil were the approval for BPH and suggestions for the early use after radical prostatectomy (23, 24). Additionally, the increase in vardenafil trend in 2011 can be explained with the international study conducted with a large patient group in this period (25). This study may have increased the interest in vardenafil on web searches. However, the interest in vardenafil in the later period appears to be less than sildenafil and tadalafil. In addition to this, there is no significant peak of avanafil trend in the last 10 years. Less generic drugs of avanafil and vardenafil compared to sildenafil and tadalafil may also have made this difference in trends (15). On the other hand, high trends of avanafil in Mediterranean countries and varde- nafil in the Eastern European and Asian countries can be investigated with further studies in these regions. Mulhall et al. indicated that patients who were previous- ly prescribed sildenafil were more likely tended to con- tinue with the same medication compared with patients who have previously prescribed tadalafil or vardenafil (26). On the other hand, there are contradictory results that show that patients are more likely to prefer tadalafil after experiencing sildenafil (27). A study from Canada showed that most patients and physicians preferred tadalafil instead of sildenafil (28). Thus, additional prospective studies are necessary to provide advanced insights into this issue. In February 2020, when the COVID-19 pandemic start- ed, a trend decreases up to 20% was observed in all PDE5i. Higher interest in COVID-19 related searches can be a reason of this decrease. Moreover, sexual behaviors seem to be negatively affected by the pandemic because of quarantine rules, multiple contact restrictions and fear of contamination (29). Karagöz et al. found that the fre- quency of sexual intercourse decreased in both sexes dur- ing the pandemic period compared to the pre-pandemic period (30). However interestingly 3 months later the trend of PDE5i came back to old levels and then started to rise again. Considering that stress and anxiety increase the frequency of ED, as well as the need of PDE5i. So, the pandemic affected the PDE5i trend both badly and well. To the best of our knowledge, this is the first study that focuses on the differences of PDE5i on Google searches from the aspect of time and geography. Our study has some limitations. Firstly, GT data are anonymous and do not give the possibility for analyzing sub-population groups. Besides, we only had access to RSV and access to raw data was not possible. Furthermore, because the internet is more popular among the young population there may be inadequate data for older men. Lastly, search terms except English languages are not consid- ered. However, we believe that our results reveal the cur- rent PDE5i search trends on the web. CONCLUSIONS In conclusion, people from different geographies search the internet for ED treatment options. Patients should be informed that ED may be the first sign of many comorbid diseases, and patients with ED should be referred to a health institution for diagnosis and treatment. 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Influence of COVID-19 pan- demic on sexuality: a cross-sectional study among couples in Turkey. Int J Impot Res. 2020 Dec 16:1-9. doi: 10.1038/s41443-020-00378- 4. Epub ahead of print. Correspondence Müslim Doğan Değer, MD Department of Urology, Edirne Sultan 1st Murat State Hospital, Edirne (Turkey) Serdar Madendere, MD (Corresponding Author) serdarmadendere@gmail.com Department of Urology, Gümüşhane State Hospital Hasanbey Mahallesi, 29000, Gümüşhane (Turkey)