Clinical study
STT is a well-known traditional herbal preparation in Thailand. In addition to its traditional use as a remedy for the effective treatment of decreased male libido, which may ameliorate erectile function, data from randomized controlled clinical trials on its efficacy and safety are lacking. The present clinical trial in 54 male patients with mild to moderate ED aged 50-69 years old for 12 weeks who received an aqueous extract of STT 1,600 mg/day or placebo was conducted as a result. This study emphasized treatment response, in terms of drug efficacy and tolerability (side effects), and treatment satisfaction, in terms of subjective patient and partner responses and overall satisfaction with treatment based on self-report questionnaires.
The five domains in the IIEF-5 questionnaire are erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Total IIEF-5 scores can be classified into five levels of severity, where a higher score represents better function; the score ranges are 5-7, 8-11, 12-16, 17-21 and 22-25 for severe, moderate to severe, mild to moderate, mild, and no ED, respectively. The score range used to recruit subjects for the study (8-21) was centered around mild to moderate [
28,
29]. The results of the IIEF-5 (Fig.
3a-b) showed that the degree of erection from initial sexual stimulation to the completion of intercourse was sufficient for penetration. The firmness increased steadily over the follow-up period, and as a result, 24 out of 27 patients in the treatment group improved from mild, mild to moderate, or moderate to severe and had normal scores by the fourth visit (week 12), corresponding to an overall cure rate of 88.9%; no such improvement was observed in the placebo group. The primary outcome was the average IIEF-5 score, which showed a significant mean difference between groups. After the mean difference was calculated, the proportion or percent of recovery change for each severity level was considered. The statistical analysis took age into account when estimating means using GLMs and performing significance tests. Controlling for the effect of age explains why the recovery rate in the placebo group was different from the value reported in previous research. A comparison of the efficacy, using IIEF-5 scores, of STT in this study (N=54) with that of
Tribulus terrestris (
N=180) [
34] and Korean Red Ginseng (N=60) [
35] for the treatment of mild to moderate ED in male patients demonstrated cure rates of 88.9, 100.0 and 66.6%, respectively. STT demonstrated potential effectiveness for the treatment of mild to moderate ED compared with that of the two herbs.
The QSF scale consists of psychosomatic quality of life, sexual activity, self-reported sexual (dys) function, and sexual (dys) function in the partners’ view [
30]. The study results for psychosomatic quality of life showed that the patients’ scores decreased from the second visit (week 4) (18.1) to the fourth visit (week 12) (16.0) in the treatment group (Fig.
5a), especially in terms of sleep problems. After treatment, the degree of sleep quality of 16 of the 27 patients improved from "moderate to no improvement". After the fourth visit, the overall scores for psychosomatic quality of life showed no difference between the treatment and placebo groups (16.0). The scores for sexual activities such as a regular sex life and desire for sexual activity (sexual intercourse or masturbation) in the QSF group increased steadily from the second visit (23.1) to the fourth visit (25.7) compared with those of the placebo group (22.0) (Fig.
5b). Meanwhile, the QSF scores reflecting desire for sexual intercourse doubled in 20 patients compared with the baseline values, and 23 patients reported masturbation. Based on the score for self-reported sexual (dys) function, including sexual dreams, fantasies, or desire, as reported by the patients and their partners, there was no difference between the groups before or after treatment (Fig.
5c). Fig.
5d shows the partner-reported sexual (dys) function scores, including sexual organ response, sexual excitement, and satisfaction during sexual activities. The results showed no difference from the second visit (7.0) to the fourth visit (6.9) in the treatment group. Similar results were also found in the placebo group. However, 18 of the 27 patients in the treatment group achieved high satisfaction during sexual activity (Question 32). Based on the improvement displayed in all five domains of the IIEF-5 (Fig.
3a-b) and the significant increase in the QSF (Fig.
4, Fig.
5a-d), the herbal extract STT helped to enhance the overall quality of sexual behavior in elderly men and the sexual satisfaction of both the patients and their partners.
Colson's report indicates that the incidence of ED increases with age [
36]. Older adult men try to find treatment either from modern medicine or traditional and alternative medicine. Recently, many research studies on ED treatment using conventional therapy and complementary and alternative medicine have been conducted both locally and globally. Ower’s study is one of several studies on the use of TTM for ED treatment; these drugs, prepared from raw materials, have been locally used for hundreds of years. Thai herbal preparations, including STT, commonly consist of various ingredients that mitigate side effects. The primary compounds in the drug used by the treatment group are alkaloids, saponins, and flavonoids, which are bioactive aphrodisiac compounds. Through the action of these compounds, STT is capable of affecting penile erection [
37]. The word “aphrodisiac” is from the Greek name "Aphrodite,” which is associated with sex, love, and beauty [
38]; accordingly, one of the primary uses of an aphrodisiac drug is to promote sexual desire. The process begins from the central nervous system, directly controlling blood flow to the male penis [
37]. The process occurs whenever there is a source of sexual stimulation such as visual fantasies, erotic thought, masturbation, or coitus. These factors stimulate the parasympathetic nerves to secrete and release nitric oxide from the smooth muscle cells of the cavernous artery. Moreover, the enzyme guanylate cyclase (GC) is stimulated to convert guanosine triphosphate (GTP) into cyclic guanosine triphosphate (cGMP). This process results in relaxation of the smooth muscle of the penis, thereby dilating the penile arteries, which causes increased blood circulation and erection of the penis. The erection of the penis can be stopped by the enzymatic hydrolysis of cGMP to GMP by phosphodiesterase type 5 (PDE5) inside the tissue. Therefore, aphrodisiacs inhibit the hydrolysis of cGMP to extend the time of erection [
8,
36,
38]. Kotta classified aphrodisiacs into three main categories based on their mechanisms [
39]. The first category provides nutritional value to improve health or well-being, leading to improved sexual performance and libido. The second exerts physiological effects on blood flow to numb the genital area during sexual activity. The third category crosses the blood-brain barrier and stimulates brain areas related to sexual arousal.
In this study, the STT herbal extract improved sexual performance by promoting sexual arousal. In particular,
B. rotunda (Krachai in Thai) is a selective inhibitor of PDEs, especially PDE5, which supports the properties of this preparation [
40]. PDE5 is the main isoenzyme of PDE associated with cGMP; its metabolic action relaxes the vessels and increases the flow of blood to the corpora cavernosa, resulting in erectile function during sexual intercourse. A recent review reported that several herbal medicines can affect penile erection through different mechanisms [
37]. The ergogenic properties of alkaloids lead to dilation of the blood vessels, causing an erection. Additionally, saponin reacts to form nitrous oxide and leads to smooth muscle relaxation via the L-arginine/nitrous oxide pathway [
37]. Finally, the presence of flavonoids in plant extracts can influence androgen levels.
In a review of scientific studies, Ongwisespaiboon and Jiraungkoorskul presented evidence that phytochemical substances or secondary plant metabolites have sexual arousal properties and can be classified into three main groups of aphrodisiacs based on their similar structures [
18]. These categories are (1) flavonoids and other phenolics, (2) alkaloids, and (3) saponins. Functionally, they can act as PDE inhibitors, particularly sildenafil, used clinically to treat male ED. The chemical compounds of the herbal preparation in STT were alpinetin, boesenbergin, cardamonin, geraniol, krachaizin, panduratin A, pinostrobin, pinocembrin, rotundaflavone, and silybin [
18] in
B. rotunda; alkaloids, saponins and flavonoids in
S. acuta; and saponins, flavonoids, and alkaloids in
D. aegyptium. During our 12-week study, STT enabled patients to achieve sexual arousal; in this manner, STT improved sexual behavior, including sexual desire, sexual motivation, sexual performance, and sexual pleasure.
O. sativa is used in Thai folk medicine as a tonic, aphrodisiac, and diuretic as well as to nourish the kidneys and spleen [
20]. Protein, B-complex vitamins, and minerals in rice help to build resilient muscles, nourish skin and blood vessels, and support the endocrine system. Furthermore, rice provides iron to increase the hematocrit; phosphorus and potassium to maintain internal water balance; and other nutrients with various functions. Thus, rice helps to restore homeostasis.
Our study also addressed the quality of sleep and quality of life by employing within-patient repeated measures for the Pittsburgh Sleep Quality Index (PSQI) and Short-Form 36 quality of life instrument (SF-36). Improvements in sleep quality were found from the second visit to the fourth visit in the QSF, PSQI, and SF-36. The total mean SF-36 scores increased steadily from the first visit (120.0) to the fourth visit (128.5) in the treatment group, while those of the placebo group were 126.1 at the first visit and 125.3 at the fourth visit. The results showed that STT improved sleep quality compared with the placebo, indicating that this herbal preparation has a beneficial effect on sleep and leads to sleep improvement because of sexual satisfaction. Testosterone levels did not significantly differ among the first, second, and third visits in either group (Table
3). Thus, STT showed no effect on testosterone levels and the same results as those in the randomized control trials of
Tribulus terrestris [
34] and Korean Red Ginseng [
35] for the treatment of mild to moderate ED in male patients.
The safety of STT in terms of blood chemistry was assessed by comparing ALT, AST, ALP, uric acid, thyroid function (T3, T4, TSH), and PSA in the periods before and after the treatment. There were no statistically significant changes in either group. The traditionally used water extracts of STTs are described as being safe, which is supported by the present trial showing no differences in all analyzed safety parameters and adverse events compared with the placebo. Negative consequences associated with treatment have been identified as important to patients receiving treatment for ED [
41]. There was no statistically significant difference in adverse event rates between the groups, and no serious adverse events were reported. Ankle, lumbar, and muscle pain was found in both groups due to physical training. Minor eye discomfort was reported during the first two days. One patient in the placebo group reported discomfort in the form of a slight headache because the patient was recovering from a cold at the time. Furthermore, eight out of 11 patients who had hypertension after taking STT at the first visit (day 0) returned to normal by the third visit (week 8) because STT may promote vasodilation, thereby decreasing the resistance to blood flow.
The participant groups were followed up during the trial using a careful tracking system, and excellent relationships were maintained with the participants. The researcher made periodic calls to the participants, provided advice and counseling during the study and made appointments, which were recorded in writing at all times. All 54 participants completed the full trial and brought back the medicine bottles at each follow-up visit; the researchers recorded the number of doses remaining at each follow-up to confirm that the capsules were taken as scheduled.
STT provides an effective and low-cost alternative ED treatment that has several advantages over other options, which are more expensive and have other adverse effects. The traditional treatments of lifestyle modifications, oral medications, injections, and penile prostheses fail to provide the desired results for a large proportion of patients suffering from ED [
6]. Novel approaches using low-intensity extracorporeal shock wave therapy (Li-ESWT), stem cell therapy (SCT), and platelet-rich plasma (PRP) to treat ED still need further investigation [
14]. Oral PDE5 inhibitors (i.e., sildenafil, tadalafil, and vardenafil) take effect within 1 hour and are active for up to 24 hours (tadalafil); however, a key disadvantage of these drugs is that they are contraindicated in men with severe cardiovascular disease and men on nitrates [
42,
43]. Additionally, PDE5 inhibitors are expensive for a first-line treatment, costing over $10 per dose [
42]. TTM is also highly effective, has no known life-threatening side effects, acts as a targeted therapy, is inexpensive, and strengthens the body while treating ED; however, patients must avoid seafood and fermented food during treatment [
44]. This research supports the traditional use of STT in elderly men for improving the quality of sexual function and demonstrates the potential to be used as an alternative therapy in patients with mild to moderate ED.