CLINICAL STUDIES ON THE FOLLOWING INGREDIENTS:

Tribulus terrestris

Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial¹

Abstract

Objective: The primary objectives were to compare the efficacy of extracts of the plant Tribulus terrestris (TT; marketed as Tribestan), in comparison with placebo, for the treatment of men with erectile dysfunction (ED) and with or without hypoactive sexual desire disorder (HSDD), as well as to monitor the safety profile of the drug. The secondary objective was to evaluate the level of lipids in blood during treatment.

Participants and design: Phase IV, prospective, randomized, double-blind, placebo-controlled clinical trial in parallel groups. This study included 180 males aged between 18 and 65 years with mild or moderate ED and with or without HSDD: 90 were randomized to TT and 90 to placebo. Patients with ED and hypertension, diabetes mellitus, and metabolic syndrome were included in the study. In the trial, an herbal medicine intervention of Bulgarian origin was used (Tribestan®, Sopharma AD). Each Tribestan^® film-coated tablet contains the active substance Tribulus terrestris, herba extractum siccum (35-45:1) 250mg which is standardized to furostanol saponins (not less than 112.5mg). Each patient received orally 3×2 film-coated tablets daily after meals, during the 12-week treatment period. At the end of each month, participants' sexual function, including ED, was assessed by International Index of Erectile Function (IIEF) Questionnaire and Global Efficacy Question (GEQ). Several biochemical parameters were also determined. The primary outcome measure was the change in IIEF score after 12 weeks of treatment. Complete randomization (random sorting using maximum allowable% deviation) with an equal number of patients in each sequence was used. This randomization algorithm has the restriction that unequal treatment allocation is not allowed; that is, all groups must have the same target sample size. Patients, investigational staff, and data collectors were blinded to treatment. All outcome assessors were also blinded to group allocation.

Results: 86 patients in each group completed the study. The IIEF score improved significantly in the TT group compared with the placebo group (P<0.0001). For intention-to-treat (ITT) there was a statistically significant difference in change from baseline of IIEF scores. The difference between TT and placebo was 2.70 (95% CI 1.40, 4.01) for the ITT population. A statistically significant difference between TT and placebo was found for Intercourse Satisfaction (p=0.0005), Orgasmic Function (p=0.0325), Sexual Desire (p=0.0038), Overall Satisfaction (p=0.0028) as well as in GEQ responses (p<0.0001), in favour of TT. There were no differences in the incidence of adverse events (AEs) between the two groups and the therapy was well tolerated. There were no drug-related serious AEs. Following the 12-week treatment period, significant improvement in sexual function was observed with TT compared with placebo in men with mild to moderate ED. TT was generally well tolerated for the treatment of ED.

Source: Kamenov Z, Fileva S, Kalinov K, Jannini EA. Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial. Maturitas. 2017 May;99:20-26. doi: 10.1016/j.maturitas.2017.01.011. Epub 2017 Feb 12. PMID: 28364864.

Tongkat Ali (Eurycoma longifolia)

Randomized Clinical Trial on the Use of PHYSTA Freeze-Dried Water Extract of Eurycoma longifolia for the Improvement of Quality of Life and Sexual Well-Being in Men²

Abstract

A randomized, double-blind, placebo-controlled, parallel group study was carried out to investigate the clinical evidence of E. longifolia in men. Primary endpoints were the Quality of Life investigated by SF-36 questionnaire and Sexual Well-Being investigated by International Index of Erectile Function (IIEF) and Sexual Health Questionnaires (SHQ); Seminal Fluid Analysis (SFA), fat mass and safety profiles. The E. longifolia (EL) group significantly improved in the domain Physical Functioning of SF-36, from baseline to week 12 compared to placebo (P = 0.006) and in between group at week 12 (P = 0.028). All safety parameters were comparable to placebo.

Source: Ismail SB, Wan Mohammad WM, George A, Nik Hussain NH, Musthapa Kamal ZM, Liske E. Randomized Clinical Trial on the Use of PHYSTA Freeze-Dried Water Extract of Eurycoma longifolia for the Improvement of Quality of Life and Sexual Well-Being in Men. Evid Based Complement Alternat Med. 2012;2012:429268. doi: 10.1155/2012/429268. Epub 2012 Nov 1. PMID: 23243445; PMCID: PMC3518798.

Ashwagandha

A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha (Withania somnifera) in Aging, Overweight Males³

Abstract

Ashwagandha (Withania somnifera) is a herb commonly used in Ayurvedic medicine to promote youthful vigor, enhance muscle strength and endurance, and improve overall health. In this 16-week, randomized, double-blind, placebo-controlled, crossover study, its effects on fatigue, vigor, and steroid hormones in aging men were investigated. Overweight men aged 40–70 years, with mild fatigue, were given a placebo or an ashwagandha extract (Shoden beads, delivering 21 mg of withanolide glycosides a day) for 8 weeks. Outcome measures included the Profile of Mood States, Short Form (POMS-SF), Aging Males’ Symptoms (AMS) questionnaire, and salivary levels of DHEA-S, testosterone, cortisol, and estradiol. Fifty-seven participants were enrolled, with 50 people completing the first 8-week period of the trial and 43 completing all 16 weeks. Improvements in fatigue, vigor, and sexual and psychological well-being were reported over time, with no statistically significant between-group differences. Ashwagandha intake was associated with an 18% greater increase in DHEA-S (p = .005) and 14.7% greater increase in testosterone (p = .010) compared to the placebo. There were no significant between-group differences in cortisol and estradiol. In conclusion, the intake of a standardized ashwagandha extract (Shoden beads) for 8 weeks was associated with increased levels of DHEA-S and testosterone, although no significant between-group differences were found in cortisol, estradiol, fatigue, vigor, or sexual well-being. Further studies with larger sample sizes are required to substantiate the current findings.

Source: Lopresti AL, Drummond PD, Smith SJ. A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha ( Withania somnifera) in Aging, Overweight Males. Am J Mens Health. 2019 Mar-Apr;13(2):1557988319835985. doi: 10.1177/1557988319835985. PMID: 30854916; PMCID: PMC6438434.

Fenugreek

Beneficial effects of fenugreek glycoside supplementation in male subjects during resistance training: A randomized controlled pilot study⁴

Abstract

Purpose To evaluate the efficacy and safety of the glycoside fraction of fenugreek (Trigonella foenum-graecum) seeds (Fenu-FG) on physiological parameters related to muscle anabolism, androgenic hormones, and body fat in healthy male subjects during an 8-week resistance training program using a prospective, randomized, double-blind, placebo controlled design.

Methods Sixty healthy male subjects were randomized to ingest capsules of Fenu-FG (1 capsule of 300 mg, twice per day) or the matching placebo at a 1:1 ratio. The subjects participated in a supervised 4-day per week resistance-training program for 8 weeks. The outcome measurements were recorded at recruitment (baseline) and at the end of the treatment (8 weeks). The efficacy outcome included serum testosterone (total and free) levels, muscle strength and repetitions to failure, metabolic markers for anabolic activity (serum creatinine and blood urea nitrogen), and % body fat. The standard safety measurements such as adverse events monitoring, vital signs, hematology, biochemistry, and urinalysis were performed.

Results Fenu-FG supplementation demonstrated significant anabolic and androgenic activity as compared with the placebo. Fenu-FG treated subjects showed significant improvements in body fat without a reduction in muscle strength or repetitions to failure. The Fenu-FG supplementation was found to be safe and well-tolerated.

Conclusion Fenu-FG supplementation showed beneficial effects in male subjects during resistance training without any clinical side effects.

Source: Wankhede S, Mohan V, Thakurdesai P. Beneficial effects of fenugreek glycoside supplementation in male subjects during resistance training: A randomized controlled pilot study. J Sport Health Sci. 2016 Jun;5(2):176-182. doi: 10.1016/j.jshs.2014.09.005. Epub 2015 Mar 7. Erratum in: J Sport Health Sci. 2018 Apr;7(2):251. doi: 10.1016/j.jshs.2018.03.001. PMID: 30356905; PMCID: PMC6191980.

Epimedium

The testosterone mimetic properties of icariin⁵

Abstract

Aim: To evaluate the testosterone mimetic properties of icariin.

Methods: Forty-eight healthy male Sprague-Dawley rats at the age of 15 months were randomly divided into four groups with 12 rats each: the control group (C), the model group (M), the icariin group (ICA) and the testosterone group (T). The reproductive system was damaged by cyclophosphamide (intraperitoneal injection, 20 mg/kg x day) for 5 consecutive days for groups M, ICA and T, at the sixth day, ICA (gastric gavage, 200 mg/kg x day) for the ICA group and sterandryl (subcutaneous injection, 5 mg/rat . day) for the T group for 7 consecutive days, respectively. The levels of serum testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), serum bone Gla-protein (BGP) and tartrate-resistant acid phosphatase activity in serum (StrACP) were determined. The histological changes of the testis and the penis were observed by microscope with hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase biotin-dUTP-X nick end labeling (TUNEL), respectively.

Results: (1) Icariin improved the condition of reproductive organs and increased the circulating levels of testosterone. (2) Icariin treatment also improved the steady-state serum BGP and might have promoted bone formation. At the same time, it decreased the serum levels of StrACP and might have reduced the bone resorption. (3) Icarrin suppressed the extent of apoptosis of penile cavernosal smooth muscle cells.

Conclusion: Icariin has testosterone mimetic properties and has therapeutic potential in the management of hypoandrogenism.

Source: Zhang ZB, Yang QT. The testosterone mimetic properties of icariin. Asian J Androl. 2006 Sep;8(5):601-5. doi: 10.1111/j.1745-7262.2006.00197.x. Epub 2006 Jun 5. PMID: 16751992.

L-Arginine

The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis⁶

Abstract

Introduction: The efficacy and safety of arginine supplements in erectile dysfunction (ED) remain debatable.

Aim: To assess the potential role of arginine supplements on ED as alternatives to phosphodiesterase inhibitors.

Methods: Studies published up to April 2018 that evaluated the efficacy of arginine supplements were identified from multiple databases (Google Scholar, PubMed, Medline, Embase, Kiss, DBpia, and Cochrane databases). Studies comparing arginine supplements with placebo or no treatment; focusing only on patients with mild to moderate severity of ED; and presenting outcomes such as improvement rate, International Index of Erectile Function (IIEF) score, and adverse effects were included. Subgroup analysis for arginine alone and arginine in combination with other substances was further conducted to increase interpretability.

Main outcome measure: The strength of the association between arginine supplements and ED was assessed using relative odds ratios and weighted mean differences with 95% CI.

Results: In total, 10 randomized controlled trials met the inclusion criteria, reporting the outcomes of 540 patients with ED. The analysis demonstrated that arginine supplements with dosage ranging from 1,500 to 5,000 mg significantly improved ED compared with placebo or no treatment (odds ratios, 3.37 [1.29, 8.77], P = .01, I2 = 44). Arginine supplements also caused significant improvements in the IIEF subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function, and erectile function, whereas the IIEF sexual desire score remain unchanged. The adverse effect rate in the arginine-treated group was 8.3%, and that in the placebo group was 2.3%, none of which were severe.

Clinical implications: Arginine supplements can be recommended to patients with mild to moderate ED.

Strength & limitations: The strength of this study is that it is the first meta-analysis to assess the potential role of arginine supplements in ED compared with placebo or no treatment. A limitation is that the treatment dosage and duration varied among studies, which may have contributed to study heterogeneity.

Conclusion: The results of our systematic review and meta-analysis provide evidence on the effectiveness of arginine supplements for mild to moderate ED. Rhim HC, Kim MS, Park Y-J, et al. The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis. J Sex Med 2019;16:223-234.

Source: Rhim HC, Kim MS, Park YJ, Choi WS, Park HK, Kim HG, Kim A, Paick SH. The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis. J Sex Med. 2019 Feb;16(2):223-234. doi: 10.1016/j.jsxm.2018.12.002. Erratum in: J Sex Med. 2020 Mar;17(3):560. doi: 10.1016/j.jsxm.2020.01.021. PMID: 30770070.

D-Aspartic acid

The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats⁷

Abstract

Background: D-aspartic acid is an amino acid present in neuroendocrine tissues of invertebrates and vertebrates, including rats and humans. Here we investigated the effect of this amino acid on the release of LH and testosterone in the serum of humans and rats. Furthermore, we investigated the role of D-aspartate in the synthesis of LH and testosterone in the pituitary and testes of rats, and the molecular mechanisms by which this amino acid triggers its action.

Methods: For humans: A group of 23 men were given a daily dose of D-aspartate (DADAVIT) for 12 days, whereas another group of 20 men were given a placebo. For rats: A group of 10 rats drank a solution of either 20 mM D-aspartate or a placebo for 12 days. Then LH and testosterone accumulation was determined in the serum and D-aspartate accumulation in tissues. The effects of D-aspartate on the synthesis of LH and testosterone were gauged on isolated rat pituitary and Leydig cells. Tissues were incubated with D-aspartate, and then the concentration (synthesis) of LH and cGMP in the pituitary and of testosterone and cAMP in the Leydig cells was determined.

Results: In humans and rats, sodium D-aspartate induces an enhancement of LH and testosterone release. In the rat pituitary, sodium D-aspartate increases the release and synthesis of LH through the involvement of cGMP as a second messenger, whereas in rat testis Leydig cells, it increases the synthesis and release of testosterone and cAMP is implicated as second messenger. In the pituitary and in testes D-Asp is synthesized by a D-aspartate racemase which convert L-Asp into D-Asp. The pituitary and testes possesses a high capacity to trapping circulating D-Asp from hexogen or endogen sources.

Conclusions: D-aspartic acid is a physiological amino acid occurring principally in the pituitary gland and testes and has a role in the regulation of the release and synthesis of LH and testosterone in humans and rats.

Source: Enza Topo, Andrea Soricelli, Antimo D'Aniello, Salvatore Ronsini, and Gemma D'Aniello. “The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats” Reproductive Biology & Endocrinology (2009) 27;7:120.

Vitamin D

Effect of vitamin D supplementation on testosterone levels in men⁸

Abstract

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 μg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3). Initial 25(OH)D concentrations were in the deficiency range (< 50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

Source: Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2011 Mar;43(3):223-5. doi: 10.1055/s-0030-1269854. Epub 2010 Dec 10. PMID: 21154195.

 

References:

1. https://www.sciencedirect.com/science/article/pii/S2095254615001271?via%3Dihub
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274257/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316093/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438434/
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191980/
6. https://pubmed.ncbi.nlm.nih.gov/16751992/
7. https://pubmed.ncbi.nlm.nih.gov/24372616/
8. https://pubmed.ncbi.nlm.nih.gov/17143054/
9. https://pubmed.ncbi.nlm.nih.gov/11996210/
10. https://pubmed.ncbi.nlm.nih.gov/28853101/