Do "Testosterone Boosters" Really Increase Serum Total Testosterone? A Systematic Review

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Do “testosterone boosters” really increase serum total testosterone? A

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Article in International Journal of Impotence Research · September 2023

DOI: 10.1038/s41443-023-00763-9
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IJIR: Your Sexual Medicine Journal www.nature.com/ijir
REVIEW ARTICLE
Do “testosterone boosters” really increase serum total
testosterone? A systematic review
1✉
Afonso Morgado , Georgios Tsampoukas2, Ioannis Sokolakis 3
, Nadja Schoentgen4, Ahmet Urkmez 5
and Selcuk Sarikaya 6
© The Author(s), under exclusive licence to Springer Nature Limited 2023
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
1234567890();,:
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.
IJIR: Your Sexual Medicine Journal; https://doi.org/10.1038/s41443-023-00763-9
INTRODUCTION Prior systematic reviews have omitted less used or novel TBs,
The term “testosterone booster” (TB) is often employed to refer to a and thus, our group performed this systematic review to fill this
heterogeneous group of herbal or nutrient-based supplements used evidence gap.
for the purpose of “naturally” increasing serum testosterone levels
[1]. Not all users of TBs who seek this effect have male hypogonadism
or symptoms suggestive of low testosterone, some are motivated MATERIAL AND METHODS
by the desire to elevate normal serum testosterone levels in order Selection criteria
to improve libido and/or sexual performance, improve athletic Our review was intended to include all relevant literature
performance and/or gain muscle mass [1]. published during the last two decades to assess if TBs increase
Many TBs are heavily marketed on social media, men’s serum total testosterone (sTT) concentration. Our group defined
magazines and in marketplaces using claims of strong efficacy “testosterone booster” as a nutrient, supplement, plant-derivative,
and are sold over the counter either as pure ingredients or or drug, used individually or in combination, with the intent to
miscellaneous blends [2–5]. The laxity of supplement regulation, increase sTT concentration.
by either the European Medication Agency or the Food and Drugs The inclusion criteria of our systematic review were: prospective
Administration, has allowed the industry to thrive in the absence clinical trial studies randomized, non-randomized or non-con-
of verification of the claims attached to their products [6]. trolled; participants aged >18 years; participants are healthy men,
Moreover, their long-term history of use and the perceived men with a chronic condition, infertile men or men with late-onset
“natural” origin of some supplements can cause users to believe hypogonadism; intervention was a TB; sTT was measured before
the potential for significant adverse effects is low, which may not and during the intervention. Exclusion criteria were retrospective
be the case [7, 8]. studies or reviews, non-biological male participants and use of
Only a limited number of systematic reviews have been testosterone replacement therapy in any form.
performed on TBs, but none has reviewed this topic as a whole
[9–13]. Some have focused on specific TBs, such as Tribulus Search strategy
terrestris [13], while others have reviewed the active ingredients This systematic review was performed in accordance with
contained in the most sold TB products [3]. the Preferred Reporting Items for Systematic Reviews and
1
Serviço de Urologia, Centro Hospitalar Universitário São João, Porto, Portugal. 2Department of Urology, Oxford University Hospital NHS Trust, Oxford, UK. 32nd Department of
Urology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. 4Urology Department, University Hospital Center Bichat Claude Bernard, Paris, France.
5
Department of Urology, St. Elizabeth’s Medical Center, Boston, MA, USA. 6Department of Urology, Gülhane Research and Training Hospital, Ankara, Turkey.
✉email: luisafonsomorgado@gmail.com
Received: 22 March 2023 Revised: 24 August 2023 Accepted: 4 September 2023

A. Morgado et al.
2
Meta-Analyses (PRISMA) checklist and was registered with in three articles with dosages ranging from 2000 to 6000 IU daily
PROSPERO (ID: CRD42022353457, “Does any testosterone over a short treatment duration (6–12 weeks) [18, 22, 23]. The two
“booster” really increase serum total testosterone?”) [14]. largest trials reported negative results when compared to both
The search was performed on August 18, 2022, and updated baseline and placebo [18, 23]. The smallest study was a 6-week trial
on June 18, 2023, and was limited to articles with an abstract in football players in Eastern Europe during winter, with the
available and date of publication after January 1, 2002. Medline objective of preventing vitamin D deficiency due to lack of sun
was the database searched. The search terms used are available exposure [22]. This trial was positive both for sTT levels
as Supplement 1. After duplicates were removed, each article’s (+5.3 ± 3.2 nmol/L vs baseline; +1.65 ± 1.9 nmol/L + 6.2% vs pla-
title and abstract were independently reviewed by two cebo after treatment) and for physical performance; however, these
reviewers, and discrepancies were resolved by mutual con- results cannot be generalized due to the specific study setting.
sensus. The full text was then retrieved, and manuscripts were One author reported twice on men with concurrent vitamin D
screened once more by two independent reviewers, and deficiency and low sTT [17, 20]. Following daily 2857 UI
excluded if the full text did not meet inclusion criteria. Data supplementation for 12 weeks, no improvement in sTT was
on year of publication, year of study, study design, funding, detected. A trial in vitamin D-deficient men with a history of
number of participants, population studied, duration of treat- chronic heart failure or who were residents in a nursing home also
ment, TB used and dosage, baseline and end-of-treatment sTT showed negative results [21].
(and free testosterone (FT) if available), method of analysis for One trial in healthy, overweight men undergoing a weight
sTT (and FT if available), and adverse effects were extracted and reduction program showed an increase in sTT concentration
collated using a spreadsheet. following daily supplementation of 3332 IU for 1 year (+2.7 ± 0.8
nmol/L vs baseline), but no significant difference was observed
Risk of bias assessment when compared to placebo [15]. As this was a small trial, this may be
The risk of bias of each included study was assessed by two review due to a lack of power to detect differences or there may have been
authors. Any disagreements were resolved by discussion. Age, interference from the reduction in body mass.
body mass index and history of diabetes mellitus were preselected Other studies were RCTs on young healthy men, men with
as confounding factors. Risk of bias was assessed using the chronic conditions such as heart failure or infertile men with vitamin
recommended tools in the Cochrane Handbook for Systematic D deficiency but all failed to show a significant difference in
Reviews of Interventions. sTT [16, 19, 21, 24].
Only one vitamin D trial reported adverse effects [19]. The most
Primary objective common adverse effect related to cholecalciferol supplementation
Our outcome of interest was the mean percentage and/or absolute was hypercalciuria, which was observed in 4.3% participants
increase in sTT concentration compared to placebo at the end of supplemented with cholecalciferol/placebo and 8.5% of partici-
treatment. Our primary objective was to review all data gathered on pants supplemented with cholecalciferol/calcium. Hypercalcaemia
TBs and determine which active ingredient, if any, could be was also reported but this effect was very rare.
considered effective. We defined “effective” as a statistically
significant increase in sTT, demonstrated in at least two indepen- Tribulus terrestris. Tribulus terrestris is a plant widely distributed
dent studies, in one of the four populations of interest (healthy men, around the world, which is native to warm temperate and tropical
male athletes, men with late-onset hypogonadism or infertile men). regions in southern Eurasia and Africa. Although it is one of the
The term “possibly effective” was also coined and was defined as a most popular and marketed TBs, only four human studies were
statistically significant increase in sTT demonstrated in just a single found on Tribulus terrestris in the last two decades, all of which had
study in one of the four populations of interest. small and heterogeneous populations [25–28]. Our findings from
the data extraction are resumed in Table 3. Two studies were
published by the same research group, both were single-arm trials
RESULTS looking at supplementation with 750 mg of Tribulus terrestris taken
Search results in three daily doses. One, performed in ageing men with late-
After the removal of duplicates, the literature search yielded 3691 onset hypogonadism, found a positive outcome after 12 weeks of
articles. Following title and abstract screening, the full texts of 99 treatment (sTT: 2.133 ± 0.1954 vs 2.837 ± 1.698 nmol/L) [26], while
articles were assessed. A total of 52 articles were included in the in the other, no statistically significant effect was noted in infertile
study and were summarized as a narrative synthesis, as data were too men [27]. The remaining two studies were RCTs: Neychev et al. did
heterogeneous to perform meta-analysis. PRISMA flowchart is not record any effect on healthy young men [25], and Fernández-
available as Supplementary Fig. 1. A total of 28 different TBs were Lázaro obtained mixed negative results in “Crossfit” athletes [28].
identified, and of the 52 included articles, 10 were related to In the latter study, no difference in sTT was found in the 750 mg/
cholecalciferol (“vitamin D”); 5 to zinc and/or magnesium; 4 to day Tribulus terrestris arm following 6 weeks of treatment.
Tribulus terrestris; 4 to creatine; 3 to Eurycoma longifolia (“Tongkat
Ali”); 3 to Withania somnifera (“Ashwagandha”); 2 to betaine; 2 to Zinc and/or magnesium aspartate. Although often sold as a
D-aspartic acid (DAA); 2 to Lepidium meyenii (“Maca”); 2 to isoflavones; combination, known as Zinc–Magnesium–Aspartate (ZMA), of the
while the remaining 16 articles were single reports. Our group five studies, all RCTs, which were found on either zinc or
reported results by TB, rather than population of interest, due to our magnesium only one article was found on the ZMA combination,
primary objective. Study and participants’ basic characteristics are which showed no effect on sTT in male athletes [29]. Another
reported in Tables 1–4. Study characteristics for creatine, β-hydroxy study looking at the effects of zinc and folic acid on fertile and
β-methylbutyrate (HMB), β-alanine, zinc, magnesium, Withania infertile men was also negative [30]. Similarly, zinc and folic acid
somnifera (“Ashwagandha”), Lepidium meyenii (“Maca”), Eurycoma given, either in combination or separately, to on men following
longifolia (“Tongkat ali”) and DAA are all compiled in Table 1. varicocelectomy demonstrated no significant effect at both 3 and
6 months [31]. The zinc-only arm had a positive effect on serum
Cholecalciferol (“vitamin D”). A total of ten randomized controlled FT, yet results were displayed only as a figure. Selenium was tested
trials (RCTs) using vitamin D supplementation were identified in combination with zinc on healthy road cyclists but again, no
[15–24]; however, the populations studied were heterogeneous. effect was detected [32]. Magnesium was tested on taekwondo-
The conclusion from the data extraction is displayed in Table 2. practicing and sedentary men with no significant result when
Studies in male athletes without vitamin D deficiency were reported compared to placebo [33].
IJIR: Your Sexual Medicine Journal

Table 1. Study characteristics for creatine, β-hydroxy β-methylbutyrate, β-alanine, zinc, magnesium, Withania somnifera (“Ashwagandha”), Lepidium meyenii (“Maca”), Eurycoma longifolia (“Tongkat ali”)
and D-aspartic acid.
Agent Authors and Country Objective Type Design Duration of Result Funding/support
year treatment
Betain Arazi (2022) Iran To investigate the effect of 2-arm, double N = 10, age 16 ± 1 years 4 weeks Significant increase in None
[49] short-term betaine blinded, crossover, Treatment group serum testosterone
supplementation on randomized (n = 10): 1.25 g of compared to baseline
muscle endurance, plasma placebo controlled betaine or placebo for and placebo conditions
lactate, testosterone and 14 days followed by at resting (5.15 ± 1.5 to
cortisol levels in handball 30 days washout period 10 ± 1.9 ng/ml, p < 0.05)
players and then crossover and after exercise
(15.2 ± 2.2 vs.

8.7 ± 1.7 ng/mL, p < 0.05)
Nobari (2021) Iran To investigate the effect of 2-arm, unknown N = 29, age 15.45 ± 0.25 14 weeks Significant increase of None
[48] betaine supplementation blinding, years testosterone in the
on development-related randomized Treatment group treatment group in mid-
hormones in professional placebo controlled (n = 14): 2 g/day season and post-season
youth soccer players Placebo group (n = 14) compared to pre-season
(5.4 ± 2.1 ng/mL and
5.9 ± 1.9 ng/mL vs
3.3 ± 1.4, respectively,
p < 0.05) while a
significant decrease was
noticed in the placebo
group in post-season
compared to pre-season
and mid-season
(2.9 ± 0.7 ng/mL vs
4.1 ± 0.6 ng/mL and
3.6 ± 1.0 ng/mL,
respectively, p < 0.05)
Creatine, β-hydroxy β- Samadi (2022) Iran To investigate the effects 2-arm, double N = 20, age 21.5 ± 1.5 4 week ANCOVA showed a None
methylbutyrate and [37] of a 7-day creatine (C) blinded, years significant difference
β-alanine loading protocol at the randomized Treatment group between the BA + C and
end of four weeks of β- placebo controlled (n = 10): 6.4 g/day of BA BA + P groups
alanine (BA) for 28 days. After the (F1,17 = 9.73, p = 0.006).
supplementation on third week, C (0.3 g/kg/ Moreover, within-group
physical performance, day) comparisons showed a
blood lactate, cognitive Placebo (n = 10) significant increase of
A. Morgado et al.
performance, and resting 6.4 g/day of BA for 28 testosterone levels in

hormonal concentrations days, after the third the BA + C group
compared to BA alone week isocaloric placebo (p = 0.001) and a non-
for 7 days significant change in the
BA + P group (p = 0.588)
Fernández- Spain To investigate the effect of 4-arm, double N = 28, age 30.43 ± 4.65 10 weeks A significant increase in None
Landa (2020) Creatine monohydrate (C) blinded, years testosterone was seen in
[36] plus HMB randomized Treatment group 1 group 3 (4.91 ± 0.87 ng/
supplementation on placebo controlled (n = 7): 0.04 g/kg/day of dL vs 5.97 ± 1.23 ng/dL,
exercise-induced muscle C p < 0.05)
damage and anabolic/ Treatment group 2
catabolic hormones (n = 7): 3 g/day of HMB
including testosterone in Treatment group 3
elite male traditional (n = 7): 0.04 g/kg/day of
rowers C plus 3 g/day of HMB
Placebo (n = 7)
Durkalec- Poland To investigate whether 2-arm, double N = 58, age 22 ± 6 years 24 weeks Significant increase in Polish National Science
Michalski supplementation with blinded, crossover, 12 weeks treatment treatment group was Center
(2016) [39] HMB affects metabolism randomized 1000 mg/day HMB; seen (+53.1 mg/dL,
inc testosterone levels in placebo controlled 12 weeks of placebo p = 0.047)
highly trained men
3
4
Table 1. continued
year treatment
Van der Merwe South To investigate the effect of 2-arm, double N = 20, age 18.7 ± 0.53 3 weeks No significant increase Not reported
(2009) [35] African creatine supplementation blinded, years in testosterone in either
on serum androgen in randomized Treatment group 1 groups (14.44 ± 2.95
male rugby players placebo controlled (n = 8*drop-out): nmol/L vs 16.69 ± 4.61
Loading dose and nmol/L, p > 0.05 in
maintenance doses of treatment group)
creatinine (50-5 g/d and
glucose) before and
after washout period of
6 weeks
Placebo group
(n = 8*drop-out):
glucose only
Hoffman (2006) United States To investigate as a 3-arm, double- N = 33, age was not 10 weeks Although no significant This study was
[34] of America secondary purpose the blinded disclosed. The first changes were seen in supported by a grant
effect of creatine and randomized group (CA) was resting total from EAS Inc., Golden,
creatine plus β-alanine placebo controlled provided with a daily testosterone CO
supplementation on the trial creatine plus β-alanine concentrations in P and
hormonal responses to supplementation CA during the 10-week
resistance training in (10.5 g/d of creatine study, a significant
athletes from the college’s monohydrate and 3.2 g/ elevation in resting
football team with at least d of β-alanine), the testosterone
2 years of resistance second group (C) was concentration was seen
training experience provided with a daily in C (20.0 ± 5.9 to
creatine supplement 24.4 ± 6.4 nmol/L,
only (10.5 g/d of p < 0.05).
creatine monohydrate),
A. Morgado et al.
while the third group

(P) was given a placebo
(10.5 g/d of dextrose)
D-Aspartic acid Crewther Poland To investigate the short- 2-arm, single N = 16, age 2 weeks No significant difference Polish Ministry for
(2018) term effects of D-aspartic blinded, 35.4 ± 7.3 years for treatment group Sport and Tourism
acid on serum biomarkers randomized Treatment group (23.1 ± 4.9 to 22.8 ± 4.7
of the reproductive axis in placebo controlled (n = 8): 3 gr of aspartic nmol/l, p < 0.05) after
male climbers acid daily treatment
Placebo group (n = 8)
Willoughby United States To determine the effects Randomized, N = 20, age 22.8 ± 4.67 4 weeks In response to Aspartic Better Body Sports;
(2013) [50] of America of resistance exercise and double-blinded years, Treatment group acid supplementation, Exercise and
D-Aspartic acid placebo-controlled (n = 10) 3 g/day of total testosterone Biochemical Nutrition
supplementation serum trial aspartic acid or placebo, (p = 0.98; effect size, Laboratory at Baylor
hormones in resistance- and heavy resistance 0.001) was not University
trained men. training. significantly changed.
Eurycoma longifolia Leitao (2021) Brazil To investigate the effect of 4-arm, double N = 38, age 47.38 ± 5.03 6 months Significant improvement Coordenação de
(“Tongkat ali”) [45] concurrent training blinded, years from baseline to 6 Aperfeiçoamento de
(aerobic exercise) and randomized Treatment group 1 months for group 2 Pessoal de Nível
supplementation with placebo controlled (n = 12): control and (278.2 ± 20.5 ng/dL to Superior – Brasil
Eurycoma longifolia on placebo 400.3 ± 38.9 ng/dL, (CAPES)
erectile function and Treatment group 1 p = 0.005), for group 3
testosterone levels in men (n = 9): control and between 1 and
with symptoms of Eurycoma longifolia 6 months
androgen deficiency and (200 mg/d) (273.3 ± 40.2 ng/dL vs
total testosterone serum Treatment group 3 370.8 ± 41,3 ng/dL,
levels equal to or less than (n = 7): concurrent p = 0.021) and 4 and
346 ng/dL training and placebo 6 months
Treatment group 4 (286.8 ± 38.1 ng/dL vs
(n = 9): concurrent 370.8 ± 41.3 ng/dL,
training and Eurycoma p = 0.012) and group 4
longifolia (200 mg/d) between baseline and
6 months (253 ± 20.5 ng/
dL vs 374.5 ± 38.9 ng/dL,

Table 1. continued
year treatment
p = 0.005) and between
4 and 6 months
(308.6 ± 35.9 ng/dL vs
374.5 ± 38.9 ng/dL,
p = 0.05)
Chan (2021) Malaysia To assess the impact of 2-arm, double N = 32, age 24.4 ± 4.7 2 weeks There was a significant This study was partly
[46] Eurycoma longifolia on the blinded, years interaction between funded by the
hypothalamic-pituitary- randomized Treatment group group and time for University of Malaya
gonadal axes in healthy placebo controlled (n = 16): testosterone (F1, postgraduate fund,

young males Eurycoma longifolia 30 = 9.039, p = 0.005). PG241-2016A
(600 mg/d) Testosterone level was
Placebo group (n = 16) 15% higher in EL
following two weeks of
consumption
Lepidium meyenii Gonzales Peru To demonstrate if effect of 3-arm, double Treatment group 1 12 weeks No independent effect The Laboratorios Hersil
(“Maca”) (2002) [43] Maca on subjective report blinded, (n = 30): on sexual desire was and the Universidad
Gonzales of sexual desire was randomized Lepidium meyenii (1.5 g/ observed with score of Peruana Cayetano
(2003) [44] because of effect on placebo controlled day) neither depression and Heredia supported this
mood or serum Treatment group 2 anxiety tests nor serum study
testosterone levels (n = 15): testosterone and
Lepidium meyenii (3 g/ oestradiol levels
day)
Placebo group (n = 12)
Withania somnifera Chauhan India To investigate the effect of 2-arm, double N = 50, age 34.32 ± 3.21 8 weeks There was a statistically Did not receive any
(“Ashwagandha”) (2020) Withania somnifera on blinded, years significant increase in funding to carry out
sexual performance of randomized Treatment group serum testosterone the study
adult males placebo controlled (n = 25): 300 mg of levels (66.52 ng/dL;
Withania somnifera −80.70 to −52.34;
twice a day for 8 weeks p < 0.0001; t‐test) when
Placebo group (n = 25) compared to placebo at
8 weeks
Lopresti (2020) Australia To investigate the stress- 2-arm, double N = 37 men, age was 60 days There was no difference This study was funded
relieving and blinded, not disclosed for men between treatment by Arjuna Natural Ltd.
pharmacological actions randomized Treatment group group and placebo
of Withania somnifera on placebo controlled (n = 19) of 240 mg (p = 0.158), but there
healthy adults Withania somnifera was a statistically
A. Morgado et al.
extract (Shoden®) significant increase in

treatment group
(54.01 ± 2.95 ng/dL,
p = 0.038)
Lopresti (2019) Australia To investigate the 2-arm, double N = 57, age 51.66 ± 1.19 16 weeks Treatment for 8 weeks This study was funded
hormonal and vitality blinded, crossover, years was significantly by Arjuna Natural Ltd.
effects of Withania randomized 8 weeks of a Withania associated with
somnifera on overweight placebo controlled somnifera extract increased levels of total
men (BMI between 25 and (Shoden®) containing testosterone
35) 21 mg of with anolide (45.58 ± 16.64 ng/dL,
glycosides a day p = 0.01) vs placebo
Zinc and/or Nematollahi- Iran To investigate the effect of 4-arm, double N = 160 men who 6 months No improvement of Kerman University of
Magnesium Mahani (2014) folic acid and zinc sulfate blinded, underwent testosterone in 6 Medical Sciences
[31] administration on serum randomized varicocelectomy for months (p < 0.05)
hormonal level (inc placebo controlled grade 3 varicocele, age
testosterone) in n/a
varicocelectomized Treatment group 1
patients (n = n/a): zinc sulfate
66 mg/d and folic acid
5 mg/d
Treatment group 2
(n = n/a): folic acid
5 mg/d
5
6
Table 1. continued
year treatment
Treatment group 3
(n = n/a): zinc sulfate
66 mg/d
Placebo (n = n/a)
Cinar (2011) Turkey To investigate the effect of Comparative, N = 30, age range 4 weeks Total testosterone Not reported
[33] magnesium unrandomized- 28–22 years increased by exhaustion
supplementation and uncontrolled study Treatment group 1 in all groups, with group
exhaustive exercise on (n = 10): 10 mg 2 showing the highest
testosterone levels of magnesium/kg/d increase
sportsmen Treatment group 2 (667.3 ± 95.2 ng/dl vs
(n = 10): 10 mg 781.4 ± 98.4 ng/dl,
magnesium/kg/d with p < 0.05)
tae-kwo-do training for
90–120 min per day,
5 days a week
Treatment group 3
(n = 10): tae-kwo-do
training for 90–120 min
per day, 5 days a week
To achieve exhaustion,
all groups underwent a
20-m shuttle run test
prior to blood sampling
Neek (2011) Iran To investigate the effect of 4-arm, double N = 32, age n/a 4 weeks Numeric differences not Not reported
[32] intensive exercise on blinded, Treatment group 1 reported (Graphic
testosterone levels and randomized (n = 8): zinc 30 mg/d illustration) -
plasma lactate in cyclists placebo controlled Treatment group 2 Significant increase in
A. Morgado et al.
who were supplemented (n = 8): selenium total testosterone in all

with oral zinc and (200 μg/day) groups -
selenium Tretment group 3 Significant difference
(n = 8): zinc–selenium between effects of
supplement exhaustion exercise on
Placebo group (n = 8) serum free testosterone
in Zn group in contrast
with other groups
(p < 0.05)
Koehler (2009) Germany To investigate the effect of 2-arm, double N = 14, age 27.0 ± 4.2 56 days Numeric differences not Not reported
[29] the zinc-containing blinded, years reported (Graphic
nutritional supplement randomized Treatment group (n = 7 illustration)
ZMA on serum placebo controlled men): 3 capsules of Within groups, no
testosterone levels in ZMA/d) statistically significant
young and healthy, Placebo group (n = 7 differences in total T
regularly exercising men men) (ZMA: p = 0.42; placebo:
p = 0.69)
Ebisch (2006) Netherland To investigate the 2-arm, double N = 87, age n/a 26 weeks No significant Zorg Onderzoek
[30] underlying mechanism of blinded, Treatment group (18 differences in
increased sperm randomized subfertile, 24 fertile testosterone between
concentration after folic placebo controlled men): folic acid (5 mg/d) pre- and post-
acid and zinc sulfate and zinc sulfate (66 mg/ intervention
intervention in fertile and d) testosterone in placebo
subfertile men Placebo group (22 [–1.0 nmol/L (–4.1 to
subfertile, 23 5.0), p > 0.05] and
fertile men) intervention group [0.2
nmol/L (–2.9 to 2.3),
p > 0.05]
*medians (25th–75th
percentile)
Their study population, design and main findings are depicted on this table. For the statistical tests used for results, please consult the original articles.
C creatine, CA creatinine plus β-alanine, BA β-alanine, HMB β-hydroxy β-methylbutyrate, P placebo, ZMA zinc magnesium aspartate.

A. Morgado et al.
7
Creatine, β-hydroxy β-methylbutyrate (HMB) and β-alanine. Creatine performed in young athletes and showed a significant increase in
is an organic compound that facilitates recycling of adenosine sTT when compared to baseline and placebo. One of the studies
triphosphate, primarily in muscle and nervous system cells. It is often used a 2500 mg/day dose for 2 weeks [49], while the other used
used to improve athletic performance. Three RCTs were found on 2000 mg/day for 14 weeks during the football season [48].
the effect of creatine supplementation on testosterone [34–36]. As
expected, all were performed on male athletes [35–37]. Two did not D-aspartic acid (“DAA”). DAA is an amino acid used in the
show any significant effect when compared to placebo [35, 36]. In biosynthesis of proteins and is currently one of the most marketed
one study, there was also a combination arm, where creatine was TBs. Two RCT of young male athletes were included on DAA
given with β-alanine, also without effect [34]. In the fourth study, [50, 51], both used 3 g/day and neither showed a significant
creatine plus β-alanine was compared to β-alanine alone on military increase in sTT levels when compared to baseline or placebo.
personnel for 4 weeks, yet no difference was found on sTT [37]. β-
Alanine alone also did not show any effect on male athletes’ sTT in a Isoflavones. Isoflavones are a class of flavonoid phenolic
small RCT [38]. compounds, often referred as phytoestrogens, as they can
In Fernandez-Landa’s RCT, creatine alone had no effect; produce biological effects via binding to estrogen receptors. They
however, a significant increase in sTT was recorded for both are found in leguminous plants such as soy and green beans
creatine in combination with HMB and HMB alone [36]. HMB has (Phaseolus vulgaris). The isoflavones from a soy-protein isolate
previously been tested in a single crossover RCT in male athletes, were compared with a milk protein isolate in a 57-day randomized
with a significant increase in sTT reported after 12 weeks crossover trial of healthy men [52]. No significant differences were
(4.85 ± 1.68 vs 5.38 ± 2.1 ng/mL) [39]. Both trials of HMB used a noted in sTT concentration between treatment arms. A proprietary
dosage of 3000 mg/day. isoflavone blend (Trinovin®, Novogen Laboratories Pty Ltd,
Australia) was tested in a small single-arm prospective trial of
Withania somnifera (“Ashwagandha”). Withania somnifera is a healthy men. There was no significant effect on sTT concentration
herb that grows in India and the Middle East and has been used following 3 weeks of treatment [53].
for centuries in traditional Indian medicine to as an aphrodisiac
and to enhance muscle strength among other uses. Three studies Other findings
were included, two in healthy men [40, 41] and another in TBs were considered “promising” if one clearly positive RCT for the
overweight men [42]. The former study was a 16-week crossover outcome of interest was available, “unclear” if a positive non-
study that included 57 overweight men, a part of which had controlled prospective study against baseline sTT was available,
biochemical late-onset hypogonadism, and there was a clear the remainder were considered as “no effect shown”. TBs
increase in sTT both when compared to baseline and placebo, yet considered The main findings from these studies are resumed in
the same author could not show the same effect versus placebo Table 4. “Unclear” and “No effect shown” TBs’ results are displayed
on a smaller 60-day trial [40]. Adverse effects were noted on both in Supplement 2 [54–63].
studies and no adverse effect was reported. The third trial was a
50 healthy men RCT which reported an increase in sTT after Promising. A proprietary blend of Punica granatum fruit rind and
8 weeks of 300 mg of Withania somnifera twice per day both Theobroma cacao seed extracts (TesnorTM, Gencor Industries Inc,
versus baseline and placebo [41]. Adverse effects were also noted, United Sates of America) was tested in a three-arm RCT of Indian
and four were reported on the treatment group (two subjects men with symptoms suggestive of late-onset male hypogonadism
experienced sleepiness, one developed mild abdominal pain, and [64]. A significant increase was reported in sTT when compared to
one low‐grade joint pain). baseline and with placebo. Moreover, there may be a positive
dose effect with a 400 mg/day dose resulting in a greater increase
Lepidium meyenii (“Maca”). Lepidium meyenii is a Peruvian than 200 mg/day.
hypocotyl that grows exclusively in the high altitudes of the Shilajit is an exudate from high mountain rocks rich in mineral
central Andes. Its root is claimed to have aphrodisiac and fertility- salts and amino acids, often used in traditional medicine. A patented
enhancing properties. Two studies on Lepidium meyenii by the purified Shilajit extract (PrimaVieTM, Kolkata, West Bengal, India) was
same research group were included, and reported the same data used for 90 days in an RCT of healthy middle-aged men with positive
with no significant results one sTT when compared to baseline or results [65]. A statistically significant increase in sTT versus baseline
placebo [43, 44]. (4.84 ± 1.54 vs 5.83 ± 1.67 ng/mL) and placebo after treatment was
recorded at 90 days, but not at 30 or 60 days. A significant decrease
Eurycoma longifolia (“Tongkat Ali”). Eurycoma longifolia is a was observed in the placebo group which is not fully expected on
flowering plant native to Indochina and Indonesia, the root of 90 days.
which is claimed to improve libido and treat infertility. Two RCTs, A commercially available non-hormonal aromatase inhibitor,
one in healthy young men (600 mg/day) [45] and the other in men hydroxyandrost-4-ene-6,17-dioxo-3-THP ether and 3,17-diketo-
with late-onset male hypogonadism (200 mg/day) [46], reported androst-1,4,6-triene (Novadex XT™, Gaspari Nutrition, United States
an increase in sTT when compared to both baseline and placebo. of America) was used in an 8-week RCT in resistance-trained men,
The one study by Leitão et al. was a 6-month four-arm RCT, and with a mean 283% increase in sTT at 8 weeks of treatment [66].
concurrent physical exercise was not observed to have an additive Results were significant when compared to placebo. No adverse
or synergistic effect to Eurycoma longifolia [45]. A prospective non- effects were reported by participants.
randomized study was also performed on Eurycoma longifolia for
men with late-onset hypogonadism with a reported positive
outcome on sTT when compared to baseline, yet a very high drop- DISCUSSION
out rate and loss-to-follow-up were observed and thus its findings When designing the present systematic review, our aim was to
can be biased [47]. scrutinize if so-called TBs could “boost” sTT concentration. Our
group found a heterogeneous group of active ingredients and
Trimethylglycine (“Betaine”). Historically, the term “betaine” was identified a total of 28 different TBs, most of which were the
reserved for trimethylglycine an amino acid derivative that occurs in subject of only one study in the last two decades.
plants commonly found in food, which has a role in regulating Our first aim was to discover if there was at least some evidence
cellular hydration and maintaining cell function. Two RCTs from two to support the bold claims made by the supplement industry
different research groups in Iran were included [48, 49]. Both were regarding testosterone increase. Thus, our primary endpoint was

8
Table 2. Study characteristics for cholecalciferol (“Vitamin D”).
Authors and Country Objective Type Design Duration of Result Support
year treatment
Maghsoumi- Iran To investigate the effects of 2-arm, triple N = 86, 12 weeks No significant effect on Unclear
Norouzabad vitamin D3 on sperm blinded, age 34.78 ± 5.29 years testosterone in treatment
(2021) [24] parameters and endocrine randomized Treatment group (n = 43): group (from 3.87 ± 2.08 to
markers in infertile men with placebo 4000 IU VD3 OD 3.95 ± 1.75, p > 0.05)
asthenozoospermia controlled Placebo (n = 43)
Michalczyk Poland To investigate the influence of 2-arm, blinded, N = 28, age n/a 6 weeks A significant difference was Institute of Sport
(2020) [22] natural sun exposure and 6 randomized Treatment group (n = 15): noticed in treatment group Sciences The Jerzy
weeks of a high dose of vitamin placebo 2000 IU cholecalciferol TDS (from 22.95 ± 6.4 nmol/L to Kukuczka Academy of
D supplementation on controlled Placebo (n = 13) 28.25 ± 3.2 nmol/L, p < 0.05) Physical Education in
parameters of testosterone in but not in the placebo group Katowice
professional football players (from 23.64 ± 3.9 nmol/L to
26.60 ± 5.1 nmol/L, p > 0.05)
Ramezani Iran To investigate the effect of 2-arm, double N = 46, 12 weeks A significant reduction of Vice-Chancellor of
Ahmadi (2020) vitamin D3 supplement on blinded, age 24.22 ± 3.44 years testosterone in treatment Research, Ahvaz
[23] serum levels of anabolic randomized Treatment group (n = 20): group (6.08 ± 1.18 to Jundishapur
hormones, cortisol, anaerobic placebo 2000 IU/day 5.26 ± 1.01, p < 0.05) University of Medical
and aerobic performance in controlled Placebo group (n = 20) Sciences
active males
Zittermann Germany To investigate whether a daily 2-arm, unknown N = 133, age: intervention: 3 years Total testosterone declined Heart and Diabetes
(2018) vitamin D3 supplement is able blinding, 55.0 ± 9.9 years; placebo: non-significantly between Center North Rhine-
to improve male sex hormone randomized 51.1 ± 10.5 years baseline and follow-up in the Westphalia, Ruhr
concentrations in patients with placebo Treatment group (n = 71): placebo group (mean University Bochum,
advanced HF and 25OHD controlled 000 IU (100 µg) difference –1.37, –2.94 to 0.19, Germany
concentrations <75 nmol/L cholecalciferol per day p = 0.084) and remained Friede Springer Herz
A. Morgado et al.
Placebo group (n = 62) constant in the vitamin D Stiftung (Berlin,

group (0.29, –2.65 to 3.22, Germany)
p = 0.845) Merck KGaA
(Darmstadt, Germany,
EMR200109-616)
DiaSorin
(Dietzenbach,
Germany)
Mielgo-Ayuso Spain To investigate the influence of 2-arm, double N = 36, age 27 ± 6 years 8 weeks No statistically significant Not reported
(2018) [18] vitamin D supplementation on blinded, Treatment group (n = 18): differences in the group-by-
the hematological and iron randomized 3000 IU of vitamin D3 OD time interaction between
metabolism profile, placebo Placebo group (n = 18) groups (p = 0.852) but there
testosterone and cortisol on controlled was a significant decrease in
elite male traditional rowers both groups (treatment: from
5.37 ± 1.5 ng/mL to
4.73 ± 1.28 ng/mL, p < 0.05;
placebo: 5.06 ± 1.41 ng/mL to
4.37 ± 0.96 ng/mL, p < 0.05)
Lerchbaum Austria To investigate whether vitamin 2-arm, double N = 100, median age 49 12 weeks No significant between-group Austrian National
(2018) D supplementation increases blinded, (39–56) years differences (–0.188, –1.50 to Bank
serum total testosterone in men randomized Treatment group (n = 47): 1.12, p = 0.776)
with low levels at baseline placebo 2857 IU vitamin D OD
controlled Placebo (n = 47)
Saha (2017) India To investigate the effect of 4-arm, double N = 228, age 20.2 ± 2.2 6 months At 6 months, the serum Indian Council of
cholecalciferol/calcium on blinded, years testosterone showed a Medical Research
skeletal muscle strength and randomized Treatment group 1 significant decline from
serum testosterone in vitamin placebo (n = 41): calcium- baseline in 180 subjects
D-deficient young males controlled carbonate (500 mg (21.2 ± 6.0 to 19.1 ± 5.9 nmol/
elemental calcium, BD for L) but no significant
6 months) and placebo differences between groups
Treatment group 2 (p > 0.05)
(n = 49): cholecalciferol

Table 2. continued
year treatment
(60,000 IU/week for 8
weeks followed by 60,000
IU/fortnightly for 4-
months) and placebo
Treatment group 3
(n = 47): cholecalciferol
(60,000 IU/week for 8
weeks followed by 60,000
IU/fortnightly for 4-

months) and calcium-
carbonate (500 mg
elemental calcium, BD for
6 months)
Placebo (n = 43): double
placebo
Lerchbaum Austria To investigate whether vitamin 2-arm, double N = 100, median age 37 12 weeks No difference within groups Austrian National
(2017) [17] D supplementation increases blinded, (27–50) after 12 weeks (treatment 0.5, Bank
total testosterone levels in randomized Treatment group (n = 49): –2.2 to 2.2, p = 0.922; placebo
healthy men placebo Oral dose of 20,000 IU 0.5, –1.9 to 2.6, p = 0.424) and
controlled vitamin D Placebo (n = 49) between groups (p = 0.497)
Heijboer (2015) The To investigate a causal link 2-arm, double Study 1, N = 92, median Study 1 – 6 Testosterone concentrations Abbott, AstraZeneca,
[16] Netherlands between vitamin D and blinded, age 63 [42–86] years to 6 weeks were not affected by the BG Medicine, Novartis,
testosterone status in men with randomized weeks Study – 16 vitamin D supplementation in Pfizer, Baxter,
heart failure (study 1), male placebo Treatment group (n = 42): weeks all 3 studies (p > 0.05) Biomerieux and
nursing home residents (study controlled 2000 IU cholecalciferol Study 3 – 16 Medcon
2) and male non-Western daily weeks
immigrants in the Netherlands Placebo (n = 44)
(study 3) Study 2, N = 49, median
age 82 [71–97] years – 16
weeks
Treatment group (n = 21):
Vitamin D3 600 IU/d, 4200
IU/w or 18,000 IU/month
Placebo (n = 22)
A. Morgado et al.
Study 3, N = 42, median

age 53 [20–70] years – 16
weeks
Treatment group (n = 16):
1200 IU vitamin D/d
Placebo (n = 16)
Pilz (2011) [15] Austria To investigate whether vitamin 2-arm, double N = 54, age 49.4 ± 10.2 52 weeks No significant difference in Not reported
D supplementation affects blinded, years total testosterone the placebo
testosterone levels in Healthy randomized Treatment group (n = 31): group (11.8 ± 4.0 nmol/l vs.
overweight men undergoing a placebo 83 μg vitamin D/d 12.7 ± 5.45 nmol/l, p = 0.355)
weight reduction controlled Placebo group (n = 23) but a significant difference in
the treatment group
(10.7 ± 3.9 nmol/l to
13.4 ± 4.7 nmol/l, p < 0.001)
A total of 10 studies were included, their study population, design and main findings are depicted in this table. For the statistical tests used for results, please consult the original articles.
9
10
Table 3. Study characteristics for Tribulus terrestris.
year treatment
Fernández- Spain To investigate whether Tribulus 2-arm, single blinded, N = 30 6 weeks No significant effect on Not
Lázaro (2022) terrestris supplementation improves randomized placebo Treatment group testosterone (5.76 ± 0.86 to reported
[13] body composition, hormonal controlled (n15): age 33.1 ± 5.7 5.75 ± 1.24 ng/dL, p > 0.05) in the
response, and performance among years, 770 mg of TT treatment group
CrossFit athletes per day
Placebo (n = 15):
age 32.9 ± 6.3
Roaiah (2016) Egypt To investigate the effect of Tribulus Single arm, N = 30, age n/a 6 weeks No significant increase in Not
[26] terrestris extract on serum uncontrolled Treatment group (n- testosterone (2500 ± 0.131 to reported
testosterone subfertile men interventional 30): 250 mg TT 2700 ± 0.240 nmol/L, p > 0.05)
Roaiah (2015) Egypt To investigate the effect of Tribulus Single arm, N = 30, age n/a 3 months A significant increase in Not
terrestris extract on testosterone of uncontrolled Treatment group (n- testosterone (2133 ± 0.1954 to reported
aging men with manifestations of interventional 30): 250 mg TT 2837 ± 1.698 nmol/L, p < 0.05)
partial androgen deficiency
Neychev Bulgaria to investigate the influence of 3-arm, unknown N = 21, age 20–36 4 weeks No significant effect of Tribulus on Not
(2005) [25] Tribulus terrestris extract on androgen blinding, randomized years testosterone (15.75 ± 1.75 nmol/l reported
metabolism in young males placebo controlled Treatment group for group 1, 16.32 ± 1.57 nmol/l for
1(n = 7): 20 mg/kg group 2, 17.74 ± 1.09 nmol/l for
body weight per placebo, p > 0.05)
day of TT
Treatment group
A. Morgado et al.
1(n = 7): 10 mg/kg

body weight per
day of TT
Control group
(n = 7)
A total of four studies were included, their study population, design and main findings are depicted in this table. For the statistical tests used for results, please consult the original articles.
TT Tribulus terrestris.

Table 4. Study characteristics for other testosterone boosters.
year treatment
Pandit (2022) [64] India To investigate the safety and 3-arm, double N = 120, age 36–55 8 weeks Significant increase of Laila Nutraceuticals,
efficacy of a novel blinded, randomized years testosterone in treatment Vijayawada, Andhra
combination of Punica placebo controlled Treatment group group 1 (12.48 ± 5.47 to Pradesh, India
granatum and Theobroma 1(n = 37): 200 mg/ 15.15 ± 6.01 nmol/L, <0.0001)
cocoa seed extracts in men d and treatment group 2
with aging males’ symptoms Treatment group (13.69 ± 5.13 to 17.05 ± 4.98
2(n = 40): 400 mg/ nmol/L, <0.0001) from
d baseline at the end of the
Placebo group study, and significantly higher

(n = 38) levels (p < 0.05) for groups 1
and 2 compared to placebo at
the end of the study
(12.96 ± 5.32 nmol/L)
Haidari (2020) Iran To investigate the effect of 2-arm, triple blinded, N = 44, age 12 weeks No significant increase in
lipoic acid on testosterone randomized placebo 33.56 ± 5.07, years testosterone for treatment
levels of infertile men with controlled Treatment group group (14.56 ± 2.85 to
idiopathic asthenozoospermia (n = 23): 600 mg of 16.60 ± 3.24 nmol/L,
lipoic acid daily p = 0.081)
Placebo group
(n = 21)
Maheshwari India To evaluate the efficacy of Single-arm, N = 50, age 12 weeks A non-significant increase in Cepham Inc, Piscataway,
(2017) [61] Furosap, a novel Trigonella interventional, 43.08 ± 7.35 testosterone was seen at the NJ, USA
foenum-graecum seed extract, uncontrolled study Treatment group: end of the study
in enhancing testosterone 500 mg of Furosap (405.19 + 156.95 to
level and improving sperm 436.34 + 189.94, p = 0.164)
profile in male volunteers
Santi (2017) [62] Italy To investigate whether long- 2-arm, investigator- N = 54, age 24 weeks No significant baseline Bayer HealthCare
term, chronic treatment with started, double 56.2 ± 4.6 years differences in testosterone
vardenafil affects adrenal and blinded, randomized Treatment group were seen and no differences
testicular steroidogenesis in placebo controlled (n = 20): Vardenafil were seen among visits,
diabetic type 2 men 10 mg twice daily between the study and the
Placebo group control group (12.5 ± 4.5 vs
(n = 22) 13.6 ± 4.5 nmol/L, at the end
of trial, respectively)
A. Morgado et al.
Pandit (2015) India The investigate the effect of 2-arm, double N = 96, age 3 months A significant increase in the Natreon Inc
purified Shilajit on blinded, randomized 49.3 ± 2.6 years treatment group was seen
testosterone levels in healthy placebo controlled Treatment group (4.84 ± 1.54 to 5.83 ± 1.67,
volunteers (n = 38): 250 mg p > 0.05) in 3 months
bid Measurement at 3 months
Placebo (n = 37) was significantly higher in the
treatment group (5.83 ± 1.67
vs 4.45 ± 1.78, p < 0.05)
Derouiche (2014) Morocco To assess the effect of virgin 2-arms, unknown N = 60, mean age 3 weeks Significant improvement in Institut Aicha Santé et
argan oil (VAO) and extra blinded, randomized, of 23.42 ± 3.85 testosterone in both groups Nutrition
virgin olive oil (EVO) on the non-placebo years (+17.37% for group 1 and
hormonal profile of androgens controlled Treatment group 1 +19.95% for group 2, p < 0.05)
and anthropometric (n = 30): Argan oil but no difference between
parameters among healthy (dose n/a) groups (p > 0.05)
adult Moroccan men Treatment group 2
(n = 30): Olive oil
(dose n/a)
11
12
Table 4. continued
year treatment
Giltay (2012) [59] The To investigate whether the n-3 4-arm, double N = 1850, age 41 months No significance in total Netherlands Heart
Netherlands fatty acids affects (EPA- blinded, randomized 68.4 ± 5.3 years testosterone levels in all Foundation, US National
eicosapentaenoic acid, DHA- placebo controlled Treatment group 1 intervention groups Institutes of Health (NIH),
docosahexaenoic acid, ALA- (n = 1212): 400 mg Borderline statistical Unilever R&D, The
alpha-linolenic acid) on of EPA-DHA and 2 significance for a decline in Netherlands Brain
testosterone levels in post- grams ALA daily testosterone levels in the Foundation, Abbott
myocardial infarction patients Treatment group 2 group treated with ALA Diagnostics
(n = 1192): 400 mg compared to placebo (of
of EPA-DHA daily −0.50 ± 0.26 nmol/L
Treatment group 3 p = 0.052)
(n = 1197): 2 grams
of ALA daily
Placebo group
(n = 1236)
Goto (2011) [58] Japan To investigate the effects of 2-arm, double N = 22, age 25 ± 1 30 days Within the treatment group, Nippon Meat Packers, Inc.,
supplementation with chicken blinded, years FT was significantly increased H. Maemura
breast meat extract (CBEX) randomization not Treatment group compared to pre-exercise
containing carnosine and reported placebo (n = 14): 20 g CBEX value (numerical data not
anserine on free testosterone controlled bid available, p < 0.05) but the
(FT) to resistance exercise in Placebo group response was similar before
young healthy men (n = 8) and after supplementation
Zhang (2009) [57] China To investigate whether the 2-arm, double N = 70, age 7 weeks No significant change was Integrated Chinese
ingestion of a herbal blinded, randomized 19.9 ± 1.0 years noted in treatment group Medicine Holdings Ltd.,
supplement called placebo controlled Treatment group (10.3 ± 46.2 ng/dL, p > 0.05) or Hong Kong, China
A. Morgado et al.
Rhodiola–Gingko Capsule (n = 34): 270 mg placebo (–9.7 ± 38.2 ng/dL,

(RGC) on endurance and RGC QDS p > 0.05)
relevant hormones in highly Placebo group
trained men (n = 33)
Cinar (2009) [56] Turkey To investigate the effects of 3-arm, interventional, N = 30, age n/a 4 weeks Testosterone levels after Not reported
calcium supplementation on non-randomized, Treatment group 1: exhaustion were significantly
serum testosterone levels in controlled 35 mg/kg/day only higher in group 2 compared
highly trained men Treatment group 2: to group 1 (731.20 ± 47.78 ng/
35 mg /kg/day of a dl vs 712.60 ± 63.10 ng/dl,
calcium gluconate p < 0.05) but the higher value
and training was in group 3
Treatment group 3: (740.40 ± 53.30 ng/dl, p < 0.05)
training only
Hoffman (2008) United States To investigate the effect of 2-arm, double N = 8, age 12 weeks Numeric differences not Not reported
[38] of America effect of b-alanine blinded, crossover, 19.7 ± 1.5 years reported (Graphic illustration)
supplementation on resistance randomized, placebo Treatment group: —no significant difference
exercise performance and controlled 1.6 g TDS of due to supplementation
endocrine changes in alanine
resistance-trained men
Willoughby United States To investigate the effects of an 2-arm, blinded, N = 16, age 8 weeks Significant increase for the Gaspari Nutrition,
(2007) [66] of America aromatase-inhibiting randomized placebo 26.11 ± 4.42 years Novedex group compared Neptune, NJ
nutritional supplement on controlled Treatment group with placebo at the 4- and
serum steroid hormones etc. in (n = 8): 72 mg/d of 8-week sampling period
young, regularly exercising AI Novedex XTTM (graphic presentation)
eugonadal men Placebo group
(n = 8)

Table 4. continued
year treatment
Che (2005) [55] China To investigate the efficacy and Single-arm, N = 40, age 3 months 21 patients received 1 course Not reported
safety of Jingui Shengqi Pill in interventional, 60.5 ± 8.5 years (3 months) had serum T
treating partial androgen uncontrolled study Treatment group: increased from 4.28 ± 0.
deficiency in aging males 3 g of crude drugs 21 μg/L to 5.13 ± 0.48, p < 0.05
19 patients received 2 courses
(2 × 3 months) had serum T
increased from 4.23 ± 0.64 μg/
L to 5.68 ± 0.33, p < 0.05

Abel (2005) [54] Switzerland To investigate whether daily 3-arm, double N = 30, age 4 weeks No significant differences Not reported
intake of two different dosages blinded, randomized 37 ± 5.8 before and after
of arginine aspartate during 4 placebo controlled Treatment group 1 supplementation (37.0 ± 5.8
weeks affects selected (n = 10): 5.7 g to 39.7 ± 7.7 for treatment
parameters performance, arginine and 8.7 g group 1, 46.6 ± 12.1 to
metabolic and endocrine aspartate 43.8 ± 8.6 for treatment group
parameters in endurance Treatment group 1 2, 38.2 ± 9.4 to 38.3 ± 8.2 for
athletes (n = 10): 2.8 g placebo group, p > 0.05)
arginine and 2.2 g
aspartate
Placebo group
(n = 10)
Dillingham (2005) United States To investigate the effects of 3-arm, unblinded, N = 35, age 8 weeks Serum testosterone was Not reported
[52] of America soy protein of varying crossover, 27.9 ± 5.7 years decreased by the low-iso SP
isoflavone content on a wide randomized Treatment group 1: ingestion relative to the MP
profile of serum reproductive controlled low-iso Soy protein ingestion (p = 0.023) and the
hormones in a sample of (SP) ingestion high-iso SPI (p = 0.020) in 1
healthy young men Treatment group 2: month
high-iso Soy
protein ingestion
Control group:
milk protein (MP)
ingestion
Gambelunghe Italy To investigate if oral 2-arm, unblinded, N = 20, age 25–30 21 days Small increase of testosterone None reported
(2003) supplementation with food non-randomized years from baseline to 21 days in
containing the aromatase Treatment group the treatment group
A. Morgado et al.
inhibitor chrysin, such as (n = 10): 1280 mg (48.8 ± 7.2 to 49.1 ± 6.0 ng/mL
propolis and honey, could of propolis and in the urine)
modify testosterone urinary 20 g of honey
levels in young, healthy males Placebo group
(n = 10)
Lewis (2002) [53] New Zealand To investigate the effect of Single arm, N = 6, age 40–53 4 weeks Reported unchanged Not reported
isoflavone extract ingestion, uncontrolled years testosterone from the basal
Trinovin, in hormonal status of interventional Treatment group: level (expressed % of basal
young healthy men 40 mg of Trinovin level) 100.0 ± 16.6
OD
Their study population, design and main findings are resumed on this table. For the statistical tests used for results, please consult the original articles.
ALA alpha-linolenic acid, CBEX chicken breast meat extract, DHA docosahexaenoic acid, EPA eicosapentaenoic acid, FT free testosterone, RGC Rhodiola–Gingko Capsule.
13
A. Morgado et al.
14
the ability of the intervention (TB) to increase sTT concentration Withania somnifera (“Ashwagandha”) and Eurycoma longifolia
when compared to placebo at end-of-treatment assessment, in at (“Tongkat Ali”) were the only herbal supplements that have shown
least one of the four specified populations of interest (healthy potential. Withania somnifera had two positive RTCs, one in
men, male athletes, men with late-onset hypogonadism and overweight men and other in healthy men [41, 42], but a third one
infertile men). It was clear from the outset that reporting an in healthy men had inconclusive results as sTT was not increased
increase versus baseline was insufficient evidence to consider a TB when compared to placebo [40]. Yet, this was a very small trial and
effective. In the case of male athletes, participation in an exercise there was a numerical, but not statistical, difference in baseline sTT
program can impact sTT and interfere with study results, as such, (472.88 ± 45.06 ng/dL vs 543.47 ± 46.29 ng/dL, p = 0.282), which in
a control group was considered essential inclusion criteria. a small trial can be attributed to a false negative. There was a clear
We favored sTT over serum FT as our group anticipated that, first, increase in sTT in the treatment group (56.01 ± 2.95 ng/dL, 11.8%)
not all studies would measure FT, and, second, that the methods [40]. Further studies may help clarify Withania somnifera role as a
used to measure FT would be considered unreliable by current TB. Eurycoma longifolia had two positive RCTs, one in middle-aged
standards. men with late-onset hypogonadism and the other in young
The four populations of interest, although unrelated, have in healthy men. The latter showed a mean increase of 122.1 ng/dL
common an interest, more or less legitimate, on TBs: to inscribe 43.8% in sTT when compared to baseline [46], while the former
sTT in order to achieve a clinical benefit. Results were not reported showed an almost identical 122 ng/mL absolute mean increase in
by population of interest, as an effect in one population was not sTT [45], yet with a lower mean relative increase (15.4%) as
generalizable to all. However, our group set a low evidentiary test participants baseline sTT was higher than in the latter study. Both
for TB efficacy, classifying a TB “potentially effective” if its outcome studies were placebo controlled but were performed on different
was shown de facto in at least one of the four populations. populations of interest. As results could not be validated for the
Although supplementation with cholecalciferol to increase same population, Tongkat Ali could not be considered an effective
testosterone is novel (almost all its included studies have been TB per our categorizations, and so was classified as “promising” for
published in the last 5 years), cholecalciferol was the most studied both healthy men and men with late-onset hypogonadism. Our
TB. Our review indicates that, at present, there is no robust findings are in accordance with a late systematic review on
evidence to support a claim that cholecalciferol increases sTT Eurycoma longifolia published in 2017 (which postdates both RCTs)
concentration. Testing occurred in mostly heterogeneous scenar- that found “convincing evidence for the prominence of Eurycoma
ios and durations of treatment, with no effect shown in almost all longifolia in improving the male sexual health”. Common herbal
trials. There was one study with a clearly positive finding [22]; extract Lepidium meyenii (“Maca”) or Trigonella foenum-graecum
however, it studied a very specific population (athletes without (“Fenugreek”) did not show any evidence of effect. Fenugreek, at
natural sun exposure during the winter season), the findings of most, in its included single-arm study, demonstrated an increase
which are not generalizable. in only FT, which did not meet our criteria for efficacy, yet a lack of
Tribulus terrestris is arguably the most well-known TB and is the statistical power cannot be excluded as this was a small study. A
subject of a few previous systematic reviews [9, 13]. Surprisingly, systematic review from 2019 concluded that both Trigonella
our group only found four articles, with none confirming Tribulus foenum-graecum (“Fenugreek”) and Withania somnifera (“Ashwa-
terrestris as effective for increasing sTT. Only one study was gandha”) were found to be promising TBs [12], yet the evidence
reported as positive, however it was a single-arm study in men supporting that claim is not that clear-cut after thorough review.
with late-onset hypogonadism, without a control group [26]. Regarding the category of “other”, as these TBs were the subject
Moreover, the sTT concentration reported at the end of treatment of only a single study, confirmation or validation of their results
was still under the normal range for most participants, which is using the findings of other studies would not be possible, which
unlikely to be sufficient to manage late-onset hypogonadism. Our was an important limitation when reviewing. A proprietary blend
results are in accordance with previous systematic reviews on of Punica granatum fruit rind and Theobroma cacao seed extracts
Tribulus terrestris. (TesnorTM, Gencor Industries Inc, United States of America) [64]
Another popular but controversial TB is ZMA. Its original study and a patented purified Shilajit extract (PrimaVieTM, Novogen
from 2000 (outside our systematic review timeline) has been Laboratories Pty Ltd, Australia) [65] were considered possibly
discredited due to funding issues disclosed during the BALCO effective TBs, as both have shown an increase to testosterone in
scandal. Only one study was found on the original combination of an RCT in middle-aged men; however, both studies were industry-
the two active ingredients, with a clear negative result [29]. funded and lack external validation. Another relevant plant-based
Studies of zinc and magnesium alone were also found, but all extract was the Jingui Shenqui pill, which was also tested in
were negative. As such, there is no evidence to support a claim middle-aged men [55], yet its study was a preliminary single-
that ZMA has testosterone-boosting properties. armed and lacked a placebo control; thus, in our assessment, the
From all performance-enhancing supplements commonly used efficacy of the Jingui Shenqui pill is unclear according to our
by athletes (creatine, HMB, β-alanine, DAA and betaine) that were predefined methodology. The same was observed for the study on
investigated as TBs, only HMB and betaine showed promise, both virgin argan oil and extra virgin olive oil [60], for which the
with two studies each on male athletes with a positive outcome methodology was unclear as participants were pre-treated with
[36, 39, 48, 49]. HMB showed a mean 70 ng/mL or 14.2% increase butter, there was a lack of a control arm and the study duration
in baseline sTT after 10–12 weeks of supplementation, while was limited to 3 weeks.
betaine showed a mean 485 ng/mL or 94.1% boost in a 2-week All other TBs identified and included in our systematic review that
study. First, it is not clear if this effect is translatable to other have not been mentioned in this discussion thus far failed to show
populations of interest, or if it is the result of a synergistic effect any evidence of efficacy in terms of increasing sTT concentrations. A
with exercise, and second, although betaine supplementation calcium gluconate study was reported by its authors as a positive
achieved an impressive result, almost doubling sTT baseline result [56], yet there is no evidence in the data provided to support
values, both studies were performed in the same country and time this claim: a statistically significant difference was not shown
frame, thus other bias cannot be excluded. External validation is between exercise alone and exercise plus calcium gluconate, thus it
recommended as betaine results appear almost “too good to be cannot be concluded that calcium gluconate could have an additive
true”. There were no indications that creatine, β-alanine and DAA or synergistic effect to exercise on sTT.
could increase sTT. This is in accordance with a DAA systematic An aromatase inhibitor available over the counter, Novadex XT™,
review in which its promise on animal studies did also not also showed promise with the largest reported increase in sTT of
translate to human studies [10]. all the included trials validated against placebo (a mean 283%

A. Morgado et al.
15
increase in sTT) [66]. Although not an androgen per se, Novadex possibly effective for male athletes. Adverse effects were rarely
XT™ does not fit the usual profile of a TB supplement as it is neither reported. Many studies presented a high risk of bias, while known
a natural product nor it is unrelated to hormonal therapy. In confounders were not accounted for, as such our conclusions
accordance with our predefined methods, this study was included should be interpreted with caution.
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 DATA AVAILABILITY
as safe by the public, as many are plant-based extracts with a long The data that support the findings of this study are available from the corresponding
history of use in traditional medicine. From all included studies, author, AM, upon reasonable request.
only eight reported on adverse effects [19, 40–42, 56, 57, 64, 66],
which is clearly underreporting. Withania somnifera appears to be
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males’ symptoms: a randomized, double-blind, placebo-controlled study. Int J COMPETING INTERESTS
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66. Willoughby DS, Wilborn C, Taylor L, Campbell W. Eight weeks of aromatase Supplementary information The online version contains supplementary material
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Correspondence and requests for materials should be addressed to Afonso
Morgado.
ACKNOWLEDGEMENTS Reprints and permission information is available at http://www.nature.com/

The author would like to acknowledge the support from the other members of the reprints
Young Academic Urologist (YAU) Male Sexual and Reproductive Health group who
are not cited as authors. Publisher’s note Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
AUTHOR CONTRIBUTIONS Springer Nature or its licensor (e.g. a society or other partner) holds exclusive
The authors confirm their contribution to the paper as follows: study conception and rights to this article under a publishing agreement with the author(s) or other
design: AM; data collection: AM, GT, IS, NS, AU, SS; analysis and interpretation of rightsholder(s); author self-archiving of the accepted manuscript version of this
results: AM, GT, IS, NS, AU, SS; draft manuscript preparation: AM, GT, IS, NS, AU, SS. All article is solely governed by the terms of such publishing agreement and
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Do “testosterone boosters” really increase serum total testosterone? A

Article in International Journal of Impotence Research · September 2023

Afonso Morgado Georgios Tsampoukas

43 PUBLICATIONS 145 CITATIONS

Ioannis Sokolakis Ahmet Urkmez

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© The Author(s), under exclusive licence to Springer Nature Limited 2023

IJIR: Your Sexual Medicine Journal; https://doi.org/10.1038/s41443-023-00763-9

Received: 22 March 2023 Revised: 24 August 2023 Accepted: 4 September 2023

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IJIR: Your Sexual Medicine Journal

performance, and resting 6.4 g/day of BA for 28 testosterone levels in

while the third group

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

extract (Shoden®) signiﬁcant increase in

who were supplemented (n = 8): selenium total testosterone in all

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

Placebo group (n = 62) constant in the vitamin D Stiftung (Berlin,

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

Study 3, N = 42, median

1(n = 7): 10 mg/kg

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

Rhodiola–Gingko Capsule (n = 34): 270 mg placebo (–9.7 ± 38.2 ng/dL,

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

IJIR: Your Sexual Medicine Journal

ACKNOWLEDGEMENTS Reprints and permission information is available at http://www.nature.com/

IJIR: Your Sexual Medicine Journal

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