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Do “Testosterone Boosters” Really Increase Serum Total Testosterone?

Testosterone boosters are heavily marketed on social media and marketplaces to men with claims to significantly increase testosterone. Lax industry regulation has allowed sales of supplements to thrive in the absence of verification of their purported benefits. Our primary objective was to systematically review all data published in the last two decades on testosterone boosters and determine their efficacy. Our outcome of interest was total testosterone increase versus placebo in four different populations: male athletes, men with late-onset hypogonadism infertile men and healthy men. Following search and screening, 52 studies were included in our review, relating to 27 proposed testosterone boosters: 10 studies of cholecalciferol; 5 zinc/magnesium; 4 Tribulus terrestris and creatine; 3 Eurycoma longifolia and Withania somnifera; 2 betaine, D-aspartic acid, Lepidium meyenii and isoflavones; while the remainder were single reports. Our findings indicate that most fail to increase total testosterone. The exceptions were β-hydroxy β-methylbutyrate and betaine, which can be considered effective for male athletes. Eurycoma longifolia, a blend of Punica granatum fruit rind and Theobroma cacao seed extracts (Tesnor™) and purified Shilajit extract (PrimaVie™) can be considered possibly effective for men with late-onset hypogonadism; Eurycoma longifolia and Withania somnifera possibly effective for healthy men; and a non-hormonal aromatase inhibitor (Novadex XT™) possibly effective for male athletes.


The term “testosterone booster” (TB) is often employed to refer to a heterogeneous group of herbal or nutrient-based supplements used for the purpose of “naturally” increasing serum testosterone levels [1]. Not all users of TBswho seek his effect have male hypogonadism or symptoms suggestive of low testosterone, some are motivated by the desire to elevate normal serum testosterone levels in order to improve libido and/or sexual performance, improve athletic performance and/or gain muscle mass [1]. Many TBs are heavily marketed on social media, men’s magazines and in marketplaces using claims of strong efficacy and are sold over the counter either as pure ingredients or miscellaneous blends [2–5]. The laxity of supplement regulation, by either the European Medication Agency or the Food and Drugs Administration, has allowed the industry to thrive in the absence of verification of the claims attached to their products [6].


Moreover, their long-term history of use and the perceived “natural” origin of some supplements can cause users to believe the potential for significant adverse effects is low, which may not be the case [7, 8]. Only a limited number of systematic reviews have been performed on TBs, but none has reviewed this topic as a whole [9–13]. Some have focused on specific TBs, such as Tribulus terrestris [13], while others have reviewed the active ingredients contained in the most sold TB products [3]. Prior systematic reviews have omitted less used or novel TBs, and thus, our group performed this systematic review to fill this evidence gap.


MATERIAL AND METHODS

Selection criteria Our review was intended to include all relevant literature published during the last two decades to assess if TBs increase serum total testosterone (sTT) concentration. Our group defined “testosterone booster” as a nutrient, supplement, plant-derivative, or drug, used individually or in combination, with the intent to increase sTT concentration. The inclusion criteria of our systematic review were: prospective clinical trial studies randomized, non-randomized or non-con trolled; participants aged >18 years; participants are healthy men, menwith a chronic condition, infertile men or men with late-onset hypogonadism; intervention was a TB; sTT was measured before and during the intervention. Exclusion criteria were retrospective studies or reviews, non-biological male participants and use of testosterone replacement therapy in any form.


DISCUSSION

When designing the present systematic review, our aim was to scrutinize if so-called TBs could “boost” sTT concentration. Our group found a heterogeneous group of active ingredients and identified a total of 28 different TBs, most of which were the subject of only one study in the last two decades. Our first aim was to discover if there was at least some evidence to support the bold claims made by the supplement industry regarding testosterone increase. Thus, our primary endpoint was  when compared to placebo at end-of-treatment assessment, in at least one of the four specified populations of interest (healthy men, male athletes, men with late-onset hypogonadism and infertile men).


It was clear from the outset that reporting an increase versus baseline was insufficient evidence to consider a TB effective. In the case of male athletes, participation in an exercise program can impact sTT and interfere with study results, as such, a control group was considered essential inclusion criteria. We favored sTT over serum FT as our group anticipated that, first, not all studies would measure FT, and, second, that the methods used to measure FT would be considered unreliable by current standards. The four populations of interest, although unrelated, have in common an interest, more or less legitimate, on TBs: to inscribe sTT in order to achieve a clinical benefit. Results were not reported by population of interest, as an effect in one population was not generalizable to all. However, our group set a low evidentiary test for TB efficacy, classifying a TB “potentially effective” if its outcome was shown de facto in at least one of the four populations.


Although supplementation with cholecalciferol to increase testosterone is novel (almost all its included studies have been published in the last 5 years), cholecalciferol was the most studied TB. Our review indicates that, at present, there is no robust evidence to support a claim that cholecalciferol increases sTT concentration. Testing occurred in mostly heterogeneous scenarios and duration's of treatment, with no effect shown in almost all trials. There was one study with a clearly positive finding [22]; however, it studied a very specific population (athletes without natural sun exposure during the winter season), the findings of which are not generalizable. Tribulus terrestris is arguably the most well-known TB and is the subject of a few previous systematic reviews [9, 13]. Surprisingly, our group only found four articles, with none confirming Tribulus terrestris as effective for increasing sTT.


Only one study was reported as positive, however it was a single-arm study in men with late-onset hypogonadism, without a control group [26]. Moreover, the sTT concentration reported at the end of treatment was still under the normal range for most participants, which is unlikely to be sufficient to manage late-onset hypogonadism. Our results are in accordance with previous systematic reviews on Tribulus terrestris. Another popular but controversial TB is ZMA. Its original study from 2000 (outside our systematic review timeline) has been discredited due to funding issues disclosed during the BALCO scandal. Only one study was found on the original combination of the two active ingredients, with a clear negative result [29].


Studies of zinc and magnesium alone were also found, but all were negative. As such, there is no evidence to support a claim that ZMA has testosterone-boosting properties. From all performance-enhancing supplements commonly used by athletes (creatine, HMB, β-alanine, DAA and betaine) that were investigated as TBs, only HMB and betaine showed promise, both with two studies each on male athletes with a positive outcome [36, 39, 48, 49]. HMB showed a mean 70ng/mL or 14.2% increase in baseline sTT after 10–12 weeks of supplementation, while betaine showed a mean 485ng/mL or 94.1% boost in a 2-week study.


First, it is not clear if this effect is translatable to other populations of interest, or if it is the result of a synergistic effect with exercise, and second, although betaine supplementation achieved an impressive result, almost doubling sTT baseline values, both studies were performed in the same country and time frame, thus other bias cannot be excluded. External validation is recommended as betaine results appear almost “too good to be true”. There were no indications that creatine, β-alanine and DAA could increase sTT. This is in accordance with a DAA systematic review in which its promise on animal studies did also not translate to human studies [10]. With an iasomnifera (“Ashwagandha”) and Eurycoma longifolia (“Tongkat Ali”) were the only herbal supplements that have shown potential. Withania somnifera had two positive RTCs, one in overweight men and other in healthy men [41, 42], but a third one in healthy men had inconclusive results as sTT was not increased when compared to placebo [40].


Yet, this was a very small trial and there was a numerical, but not statistical, difference in baseline sTT (472.88 ± 45.06 ng/dL vs 543.47±46.29ng/dL, p=0.282), which in a small trial can be attributed to a false negative. There was a clear increase in sTT in the treatment group (56.01 ±2.95ng/dL, 11.8%) [40]. Further studies may help clarify With an iasomnifera role as a TB. Eurycoma longifolia had two positive RCTs, one in middle-aged men with late-onset hypogonadism and the other in young healthy men. The latter showed a mean increase of 122.1ng/dL 43.8% in sTT when compared to baseline [46], while the former showed an almost identical 122ng/mL absolute mean increase in sTT [45], yet with a lower mean relative increase (15.4%) as participants baseline sTT was higher than in the latter study. Both studies were placebo controlled but were performed on different populations of interest. As results could not be validated for the same population, Tongkat Ali could not be considered an effective TB per our categorizations, and so was classified as “promising” for both healthy men and men with late-onset hypogonadism.


Our findings are in accordance with a late systematic review on Eurycoma longifolia published in 2017 (which postdates both RCTs) that found “convincing evidence for the prominence of Eurycoma longifolia in improving the male sexual health”. Common herbal extract Lepidium meyenii (“Maca”) or Trigonella foenum-graecum (“Fenugreek”) did not show any evidence of effect. Fenugreek, at most, in its included single-arm study, demonstrated an increase in only FT, which did not meet our criteria for efficacy, yet a lack of statistical power cannot be excluded as this was a small study. A systematic review from 2019 concluded that both Trigonella foenum-graecum (“Fenugreek”) and Withania somnifera (“Ashwa gandha”) were found to be promising TBs [12], yet the evidence supporting that claim is not that clear-cut after thorough review. Regarding the category of “other”, as these TBs were the subject of only a single study, confirmation or validation of their results using the findings of other studies would not be possible, which was an important limitation when reviewing. A proprietary blend of Punica granatum fruit rind and Theobroma cacao seed extracts (TesnorTM, Gencor Industries Inc, United States of America) [64] and a patented purified Shilajit extract (PrimaVieTM, Novogen Laboratories Pty Ltd, Australia) [65] were considered possibly effective TBs, as both have shown an increase to testosterone in an RCT in middle-aged men; however, both studies were industry funded and lack external validation. Another relevant plant-based extract was the Jingui Shenqui pill, which was also tested in middle-aged men [55], yet its study was a preliminary single armed and lacked a placebo control; thus, in our assessment, the efficacy of the Jingui Shenqui pill is unclear according to our predefined methodology.


The same was observed for the study on virgin argan oil and extra virgin olive oil [60], for which the methodology was unclear as participants were pre-treated with butter, there was a lack of a control arm and the study duration was limited to 3 weeks. All other TBs identified and included in our systematic review that have not been mentioned in this discussion thus far failed to show any evidence of efficacy in terms of increasing sTT concentrations. A calcium gluconate study was reported by its authors as a positive result [56], yet there is no evidence in the data provided to support this claim: a statistically significant difference was not shown between exercise alone and exercise plus calcium gluconate, thus it cannot be concluded that calcium gluconate could have an additive or synergistic effect to exercise on sTT. An aromatase inhibitor available over the counter, Novadex XT™, also showed promise with the largest reported increase in sTT of all the included trials validated against placebo (a mean 283%  increase in sTT) [66]. Although not an androgen per se, Novadex XT™ does not fit the usual profile of a TB supplement as it is neither a natural product nor it is unrelated to hormonal therapy.


In accordance with our predefined methods, this study was included in the review as it did not meet any exclusion criteria. Identifying adverse effects was a secondary objective of the systematic review. These substances are often generally regarded as safe by the public, as many are plant-based extracts with a long history of use in traditional medicine. From all included studies, only eight reported on adverse effects [19, 40–42, 56, 57, 64, 66], which is clearly underreporting. Withania somnifera appears to be safe in the short term as three RCTs reported no to rare minor adverse effects [40–42].


Regarding adverse effects reported, it is noteworthy that long-term vitamin D supplementation caused hypercalciuria in 4.3–8.5% of participants following 6 months of treatment [19]. Regarding the risk of bias assessment, some studies were single-armed and the lack of placebo control group conferred a high risk of bias. Moreover, some included RCT did not provide sufficient information on random sequence generation, or else a high-risk method was reported. Incomplete outcome data was also identified in a few studies as data were only reported as a f igure, preventing the checking of numerical data.


Looking specifically at “potential” and “possible” TBs: the two studies on HMB had an unclear risk of bias, mainly due to a lack of information regarding sequence generation; both studies on betaine had a low risk of bias; and all the studies on possible TBs (blend of Punica granatum fruit rind and Theobroma cacao seed extracts, purified Shilajit extract and the non-hormonal aromatase inhibitor) had high risk of bias, as all trials were small-scale and industry-funded. Moreover, one preselected confounder, medical history of diabetes mellitus, was not accounted for in almost any of the studies. Diabetes mellitus is a known risk factor for late onset male hypogonadism and should have been controlled for, particularly in studies regarding middle-aged men. Our systematic review is clearly limited by the level of available evidence. Most of the identified TBs were the subject of only one study, and of these, most had a high overall risk of bias and heterogeneous populations and methodologies that limit the ability to synthesize the evidence found.


The use of medical subject headings in our search string may have narrowed the returned results, leading to the omission of studies improperly indexed. Although significant increases in sTT were noted in a few TBs, a threshold for a clinically significant increase is yet unknown and thus it may not have the desired clinical effect. Although some studies have assessed if an increase in sTT did translate in relevant clinical outcomes, whether through male hypogonadism symptoms questionnaires or physical performance tests, these reports were far inconsistent and heterogeneous; our group did not at this point in time decide to take them into account in our systematic review. A key strength is that this is the first systematic review on TBs collectively that was properly designed and conducted. All identified abstracts and full texts were reviewed twice before being selected for inclusion by a group of well-trained reviewers.


CONCLUSIONS

Our extensive systematic review has concluded that most TBs fail to demonstrate their ability to increase sTT under RCT conditions. Notable exceptions were HMB and betaine, which can be considered effective TBs in male athletes. Eurycoma longifolia (“Tongkat Ali”), a proprietary blend of Punica granatum fruit rind and Theobroma cacao seed extracts (Tesnor™) and a patented purified Shilajit extract (PrimaVie™) can be considered as possibly effective TBs for men with late-onset hypogonadism; Withania somnifera (“Ashwagandha”) and“Tongkat Ali” possibly effective for healthy men; and a non-hormonal aromatase inhibitor (Novadex XT™)  possibly effective for male athletes. Adverse effects were rarely reported. Many studies presented a high risk of bias, while known confounders were not accounted for, as such our conclusions should be interpreted with caution.


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