The Effects of Geranylgeraniol Supplementation on Testosterone in Middle-Aged Healthy Adults: An 18-Week, Single-Group Crossover Placebo-Controlled Trial

Michael Jurgelewicz, DC, MS, LDN, CNS; Christopher R. D’Adamo, PhD; Christopher A. Malaya, DC, PhD

Abstract

Background: Geranylgeraniol (GG) is a naturally occurring isoprenoid that is involved in steroid hormone synthesis, the endogenous production of coenzyme Q10 (CoQ10), healthy muscle function, bone metabolism, and cellular energy production. Although preclinical research and a recent human study have indicated a potential role for GG in modulating testosterone levels, its effects in middle-aged adults remain unclear.

Aim: This study aimed to assess the effects of GG supplementation on testosterone status, coenzyme Q10 concentrations, and validated questionnaires of overall and sexual health in middle-aged healthy adults.

Method: This 18-week, single-group, crossover, placebo-controlled trial involved participants aged 40 to 65 years. The intervention consisted of 8 weeks of placebo followed by a 2-week washout and 8 weeks of GG supplementation (300 mg/day). Outcomes were assessed at baseline, Week 8 (after blinded placebo), Week 10 (post-washout), and Week 18 (after blinded intervention).

Results: Thirty-four participants completed the study. No significant changes were observed in total testosterone, free testosterone, or sex hormone binding globulin (all P > .05) in the full study sample or within the female subgroup. In the subgroup of men with lower baseline testosterone (<600 ng/dL, n = 8), total testosterone increased significantly following GG supplementation (mean difference = 28.44 ng/dL, 95% CI: 7.45–49.43, P = .015), with a large effect size (Cohen’s d = 1.13), indicating a meaningful physiological response. Serum CoQ10 declined significantly during placebo (mean difference = −0.10 µg/mL, P = .03) but remained stable during GG supplementation (P = .9), suggesting a potential maintenance effect.

Conclusion: These results highlight GG as a promising natural strategy to support endogenous testosterone production and CoQ10 homeostasis in age-related declines. Further investigation in larger, targeted populations such as men with late-onset hypogonadism or individuals on statin therapy is warranted.

Keywords: testosterone; annatto; hypogonadal; ubiquinone, coenzyme Q10, geranylgeraniol

Michael Jurgelewicz, DC, MS, LDN, CNS, Human Nutrition Institute, University of Bridgeport, CT, USA; Parker University, Dallas, TX, USA. Christopher R. D’Adamo, PhD, Department of Family and Community Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; OvationLab, Richmond, VA, USA. Christopher A. Malaya, DC, PhD, Parker University, Dallas, TX, USA.

Corresponding author: Michael Jurgelewicz, DC, MS, LDN, CNS  

E-mail: mjurgele@bridgeport.edu

Introduction

Testosterone is a critical steroid hormone that plays an essential role in modulating sexual function, muscle mass, bone density, mood, and overall metabolic health in both men and women.¹ Testosterone deficiency is a common clinical concern, affecting approximately 10% to 40% of the global population.² In men, testosterone levels begin to decline around the age of 40 at a rate of about 1% annually, with up to 30% of men aged 40–79 experiencing deficiency.^3,4 In women, age-related testosterone insufficiency often occurs during the perimenopausal years and post-menopause, yet this generally remains underrecognized in clinical practice.^5,6 Symptoms of testosterone deficiency include fatigue, poor concentration, depression, decreased bone density, reduced libido, erectile dysfunction, and adverse changes in body composition.^2,3 In both sexes, testosterone insufficiency has been associated with cardiovascular disease and diminished quality of life.⁴

The age‐related decline in circulating testosterone levels is well documented and has prompted the development of various interventional strategies aimed at mitigating these deficiencies and restoring endocrine balance.^7,8 Testosterone replacement therapy (TRT) is the standard treatment, but not without limitations. TRT can be invasive, requires long-term compliance, and carries risks including polycythemia, prostate concerns, fertility suppression, and dermatologic reactions.^3,9 These drawbacks highlight the need for safe, non-hormonal alternatives.

In recent years, there has been an increasing focus on naturally occurring compounds with the potential to modulate steroidogenesis. Geranylgeraniol (GG) has emerged as a promising candidate for its biochemical properties and clinical evidence.^8,11 GG is a low-molecular-weight isoprenoid endogenously synthesized via the mevalonate pathway and naturally found in annatto seeds, flaxseeds, olive oil, and sunflower oil; it plays a vital role in coenzyme Q10 production, steroid hormone biosynthesis, bone metabolism, and cellular energy production.^12,13 Preclinical evidence suggests that GG upregulates testosterone production in murine testicular cells through cAMP/protein kinase A signaling.⁷ A review of in vitro and animal studies has also demonstrated GG’s ability to stimulate testosterone and progesterone synthesis.¹³

As a dietary supplement, GG is sourced from annatto and is recognized for its generally favorable safety profile that further underpins its potential application in therapeutic endocrine modulation.⁸ Given that cholesterol serves as the substrate for all steroid hormones, including testosterone, the participation of GG in cholesterol metabolism and protein prenylation suggests that it may exert a modulatory influence on steroidogenic pathways.^7,10

The safety of GG supplementation has been established up to 406 mg/day in toxicological studies,¹² and a recent human trial reported no significant alterations in sex hormone profiles in the full study sample at escalated doses (150 and 300 mg/day) in adults between 30 and 49 years.⁸ However, men with lower baseline testosterone levels (<700 ng/dL) experienced testosterone enhancement.⁸ Given these findings, evaluating GG at a higher, consistent dose in an age range associated with age-related testosterone insufficiency is warranted.

The current study is the first placebo-controlled crossover trial designed to assess the effects of 300 mg/day GG supplementation on testosterone status, coenzyme Q10 concentrations, and validated questionnaires of overall and sexual health in healthy adults between 40 and 65 years.

Materials And Methods

Study Design and Protocol

This study was conducted at a single site as an 18-week, placebo-controlled, crossover clinical trial designed to evaluate the effects of GG supplementation on testosterone status and self-reported outcomes in healthy middle-aged men and women. The protocol was approved by Pearl Institutional Review Board (Protocol #2024-0433) and registered with ClinicalTrials.gov (NCT06747624). Before engaging in any study procedures, participants signed an IRB-approved informed consent form. Participants received a placebo (300 mg medium chain triglycerides [MCT] oil in a softgel visually identical to the active study product) for eight weeks, followed by a 2-week washout period with no intervention and crossover to Annatto-GG™ 300 (300 mg of GG provided by Designs for Health, Inc.) for an additional eight weeks (Figure 1).  All participants received a placebo during the first 8-week intervention period. This sequencing decision was made because the pharmacokinetics and potential carryover effects of GG supplementation in humans are not well characterized. By administering a placebo first, we eliminated the possibility that residual or prolonged biological effects of GG could influence baseline or early study measurements. The washout period between phases was retained to preserve blinding.

The study was single-blind, since participants were unaware of whether they were receiving the study product or a placebo; however, the study investigators were aware of the allocation. To maintain participant blinding, the participants received standardized instructions and interactions that were identical between both intervention phases. Allocation concealment was maintained by utilizing sequentially numbered bottles identical in appearance (i.e., bottle size, softgel size, gelatin color, etc.) that contained the study product.

Participants were instructed to take one softgel daily with breakfast. Compliance was monitored via participant diaries. Adverse events were also recorded in daily diaries and reviewed at the end of both 8-week periods.

Study outcomes included laboratory measures of sex hormones and CoQ10 status as well as validated, patient-reported outcomes assessing overall health and sexual health. Outcomes were assessed at baseline, Week 8 (after blinded placebo), Week 10 (post-washout), and Week 18 (after blinded intervention). The primary outcomes were serum total testosterone, measured by liquid chromatography–tandem mass spectrometry (LC/MS-MS), and serum free testosterone, measured directly. Total testosterone provides a specific measure of androgen status in men and women and assists in the diagnosis of androgen dysfunction; free testosterone represents the unbound and biologically active fraction. Secondary outcomes included serum sex hormone–binding globulin (SHBG) and coenzyme Q10 (CoQ10). SHBG is the blood transport protein for testosterone and estradiol. It is a useful supplementary parameter in the determination of androgen, where a high concentration of free androgen (i.e., testosterone) is suspected. CoQ10 is endogenously synthesized via the mevalonate pathway, and some is obtained in the diet from meat products. It is also a powerful lipid-soluble antioxidant and protects cell membranes and lipoproteins.¹⁴ Validated patient-reported outcomes included the Short Form-12 Health Survey (SF-12) and the PROMIS Sexual Function and Satisfaction (SexFS v2.0) questionnaires. The SF-12 is an indicator of overall health status across eight scales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Items were scored and weighted according to the standard SF12 algorithm to generate norm-based Tscores (mean 50, SD 10), with higher scores indicating better physical or mental health status. The SF12 has demonstrated good reliability with other health-related quality-of-life indices in the general population.¹⁵ The SexFS questionnaires are sex-specific (SexFS – Female and SexFS – Male) and assess sexual interest, desire, erectile (male) or lubrication (female) function, orgasm ability and satisfaction, and sex-life quality over the past 30 days. Each domain is scored using item response theory (IRT)–based calibrations and reported as Tscores (mean 50, SD 10), where higher scores reflect better functioning or satisfaction. These measures have shown strong internal consistency and good construct validity in general populations.¹⁶ The questionnaires were administered electronically via REDCap. Data were entered into a password-protected database.

Figure 1. Study Process. Single-Group Crossover Placebo-Controlled Study Design

Note: Participants completed baseline assessments followed by 8 weeks of blinded placebo supplementation; mid-testing was conducted at 8 and 10 weeks before and after a 2-week washout period, followed by 8 weeks of blinded GG supplementation. Laboratory assessments included total testosterone, free testosterone, SHBG, and CoQ10. Patient-reported outcomes included SF-12 and PROMIS SexFS v2.0 questionnaires. Compliance diaries and adverse event monitoring were conducted throughout each phase.

Study Participants

Men and women aged 40 to 65 years were recruited via word of mouth, online, email, and directly from the Hartford County, Connecticut, area (e.g., local gyms, online, etc.) between January 24, 2025, and May 6, 2025.

Eligible participants were males and females between 40 and 65 years of age, with no significant history of inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), celiac disease, peptic ulcers, liver or kidney disease, or any other acute or chronic condition. Additional requirements included the ability to read and speak English, and a willingness to participate in the study voluntarily and provide informed consent. Female participants were required to have a negative pregnancy test confirmed by serum quantitative HCG at both the baseline assessment and the start of the crossover phase (Week 10).

Exclusion criteria were established based on clinical and scientific considerations. Individuals were excluded if they were younger than 40 or older than 65 years, had used hormone replacement therapy within the past 60 days, or had free testosterone levels above the normal reference range. Those with a history of hysterectomy, oophorectomy, or orchiectomy were excluded, along with participants taking biotin supplements exceeding 3 mg/day within 1 week of enrollment. Additional exclusions included current or history of smoking, use of CoQ10 or ubiquinol within the past 2 weeks, or use of hormone-boosting supplements (e.g., fenugreek, shilajit, tongkat ali, ashwagandha) within the past 4 weeks. Use of certain medications, such as NSAIDs, statins, blood thinners, H2 blockers, proton pump inhibitors, or glucose-lowering agents, was not permitted. Individuals with diabetes, cancer, hemophilia, or disorders of cardiac, renal, pulmonary, or hepatic function were also excluded, along with those with active infectious diseases or alcohol or drug abuse (>7 drinks per week). Pregnancy, lactation, or intention to become pregnant within the next six months were excluded. Finally, individuals were excluded if they failed to provide written informed consent or had participated in another clinical trial within the past 30 days.

For sample size estimation, an a priori power analysis (G*Power, version 3.1.9.7, Heinrich Heine University Düsseldorf, Düsseldorf, Germany) was performed with the following α, power, and effect size values. The test family was set as t tests, and the statistical test was the difference between two dependent means (matched pairs) with the following parameters: α = 0.05, 1 – β = 0.80, effect size of 0.5. The sample size was estimated to be 34. To account for potential dropouts, the sample size was increased by 10%. Hence, 38 participants were enrolled to achieve the target sample size.

After study completion, a post hoc power analysis (G*Power, version 3.1.9.7) was conducted to assess the statistical power of the exploratory analysis. The test family was specified as t tests, with the statistical test set to means: differences between two dependent means (matched pairs).

 Blood Biochemistry

Participants reported to a laboratory site at baseline, Week 8, Week 10, and Week 18 for blood collection following an overnight fast of approximately 10 hours. Venous blood was obtained via sterile venipuncture of the antecubital vein by a certified phlebotomist using a 21-gauge needle and collected into two red-top vacutainer tubes and one serum separator tube (SST). One red-top sample was transferred to an amber transfer tube, labeled as serum, and stored at -80°C until analysis. The second red-top sample and the SST were transferred to standard transfer tubes, labeled as serum, and maintained at room temperature for immediate processing. These samples were analyzed for total testosterone, free testosterone, SHBG, and CoQ10. All assays were performed at LabCorp, a CAP-accredited and CLIA-certified laboratory.

Adverse Events

Participants were instructed to record any adverse events in a daily diary and contact the principal investigator for any serious adverse events. In the event of a severe adverse event (i.e., life-threatening event, hospitalization, disability, or permanent impairment), the principal investigator was required to immediately report the event to the study sponsor and discontinue the trial.

Statistical Analysis

Descriptive statistics were computed to describe the study sample. Before conducting inferential analyses, data were screened for outliers and assessed for normality. Outliers were identified by visual inspection of box plots and by evaluating studentized residuals (values exceeding ±3 SD were considered outliers). Normality was first examined graphically using Q–Q plots and subsequently confirmed with the Shapiro–Wilk test (P > .05).

Following outlier and normality testing, mean changes in primary and secondary laboratory outcomes from baseline to study completion were compared across study arms using paired t tests with correction for repeated analyses via SPSS version 30 (IBM Corp., Armonk, N.Y., USA). To evaluate differences between study arms at different timepoints, self-reported questionnaire outcomes were analyzed using repeated-measures ANOVA with Tukey’s pairwise post hoc comparisons using SAS version 9.4.1 (Cary, NC., USA). Statistical significance was set a priori at P < .05.

Paired t tests were performed to assess the mean changes in total and free testosterone. Cohen’s d effect size was calculated, and values were interpreted as 0–0.2 (trivial), 0.2–0.5 (small), 0.5–0.8 (moderate), and >0.8 (large).¹⁷

Exploratory Analysis

Testosterone replacement is most targeted for men in the lower range of the reference values for testosterone or men who are hypogonadal. Therefore, using an exploratory analysis, the research team sought to investigate whether testosterone levels in participants affected the efficacy of GG treatment. This approach and rationale were based on the previous research of Gheith et al. (2023).⁸ For this male-specific analysis, the research team used the total testosterone normal reference range values of 264 to 916 ng/dL to form quartiles. The quartiles are as follows: Q1 = 427 ng/dL and below, Q2 = 428 to 590 ng/dL, Q3 = 591 to 753 ng/dL, Q4 = 754 ng/dL and above. To have a round cutoff, males with baseline total testosterone levels >600 ng/dL were excluded from this analysis, to focus on participants in the lower quartile ranges. We also analyzed female testosterone data, applying the same method with the reference range for adult females of 7 to 55 ng/dL. This established a Q2 upper limit of 32 ng/dL.

Results

The CONSORT participant flow diagram is provided in Figure 2. Out of 38 participants enrolled in the study, 34 completed the trial and were included in the analyses (89.5%). The demographic characteristics of the sample are provided in Table 1. The mean age of the sample was 51.3 years, with a mean BMI of 26.5 kg/m², and there were more females (58.8%) than males (42.2%). For the first 8-week period, 28 of 34 participants (82%) completed their diaries, and for the second 8-week period, 30 of 34 participants (88%) completed their diaries. Among participants who did not return compliance records, verbal self-reports indicated that the study product was taken as instructed each day. Overall, compliance with supplementation was high across both treatment periods.

Table 1. Baseline Descriptive Characteristics

 Note: Data are mean (standard deviation).

Abbreviation: BMI, body mass index.

Figure 2. Participant Flow Diagram

Male Hormone Panel

Among male participants (n = 14), paired-samples analyses revealed no significant changes in total or free testosterone during the placebo phase (P > .05). Specifically, total testosterone (mean difference = −2.32 ng/dL, 95% CI: −48.8 to 44.1, P = .92) and free testosterone (mean difference = −0.04 pg/mL, 95% CI: −1.06 to 0.97, P = .93) remained relatively stable across placebo periods (Tables 2 and 3).

Table 2. Male Hormone Panel (n = 14)

Note: Data are mean (standard deviation).

Abbreviations: GG, geranylgeraniol; PLA, placebo; Wk, week.

Table 3. Paired Samples t tests for Male Participants (n = 14)

^aP < .05.

Note: Values represent mean differences (post–pre) with corresponding 95% confidence intervals.

Abbreviations: SHBG, sex hormone–binding globulin; P, placebo period; A, active period; P2, placebo period 2 end; P1, placebo period 1 end; A2, active period 2 end; A1, active period 1 end.

Table 4. Female Hormone Panel (n = 20)

Note: Data are mean (standard deviation).

Abbreviations: GG, treatment group; PLA, placebo group.

Table 5. Paired Samples t tests for Female Participants (n = 20)

Note: Values represent mean differences (post–pre) with corresponding 95% confidence intervals.

Abbreviations: SHBG, sex hormone–binding globulin; P, placebo period; A, active period.

During active supplementation, total testosterone showed no meaningful change (mean difference = 23.8 ng/dL, 95% CI: −42.3 to 89.9, P = .45), and free testosterone did not change significantly (mean difference = 0.34 pg/mL, 95% CI: −1.45 to 2.12, P = .69).

Notably, SHBG decreased significantly during the placebo phase (mean difference = −3.04 nmol/L, 95% CI: −5.96 to −0.12, P = .042), whereas no significant changes were observed during the active phase (mean difference = 1.91 nmol/L, 95% CI: −2.23 to 6.04, P = .337). Since this effect occurred during the placebo phase and was not replicated in the active treatment phase, it is unlikely to represent a true physiological effect of the intervention. This finding may reflect random variation or assay variability. No other significant within-group differences were observed in men.

Female Hormone Panel

Among female participants (n = 20), paired samples t tests revealed no significant changes in total or free testosterone across either the placebo or active supplementation periods (P > .05). Specifically, free testosterone showed small, non-significant decreases in the placebo (mean difference = 2.60 ng/dL, P = .33) and active supplementation phase (mean difference = 2.76 ng/dL,
P = .224). Total testosterone values remained stable, with negligible mean changes across placebo (mean difference = -0.03 pg/mL, P = .909) and active periods (mean difference = 0.22 pg/mL, P = .234). SHBG demonstrated an upward trend during the placebo phase (mean difference = 8.96 nmol/L, P = .059), which approached but did not reach statistical significance, and a non-significant increase during the active supplementation phase (mean difference = 3.76 nmol/L, P = .53)

CoQ10 Concentrations

Paired-samples t tests were used to evaluate changes in serum CoQ10 concentrations across placebo and active supplementation phases (n = 33). One participant was excluded from the CoQ10 analysis due to improper sample collection, which precluded laboratory quantification; therefore, complete paired data were available for 33 participants. During the placebo phase, there was a small but statistically significant decrease in CoQ10 (mean difference = −0.10 µg/mL, 95% CI [−0.19, −0.01], P = .026). In contrast, during the active supplementation phase, no significant change was observed (mean difference = −0.004 µg/mL, 95% CI [−0.07, 0.07], P = .902) (Tables 6 and 7).

Table 6. Descriptive Statistics for Coenzyme Q10 Concentrations

Note: Valid N (listwise) = 33. Reference range for serum CoQ10: 0.37–2.20 µg/mL.

Abbreviations: P, placebo period; A, active supplementation period; SD, standard deviation.

Table 7. Paired Samples t tests for Serum Coenzyme Q10 Concentrations  (n = 33)

^aP < .05.

Abbreviations: P, placebo period; A, active supplementation period.

Patient-Reported Outcomes

There were no meaningful changes in the SF-12 or PROMIS SexFS v2.0 questionnaires across study timepoints (P > .05). For the SF-12 Physical Component Summary (PCS-12), mean scores were stable over the four assessments (Period 1 Baseline: 52.5 ± 8.3; Period 1 End: 54.0 ± 6.1; Period 2 Baseline: 53.8 ± 7.0; Period 2 End: 54.3 ± 6.3). Repeated measures ANOVA revealed no significant effect of time on PCS-12 [F(3,116) = 0.41, P = .75]. Comparable patterns were observed for the SF-12 Mental Component Summary (MCS-12) and PROMIS Sexual Function domains, with mean scores remaining consistent and no statistically significant differences detected across timepoints (all P > .05).

Adverse Events

A total of 5 participants reported adverse events (GG = 3, PLA = 2), all mild in severity and resolved without intervention. There was one report of emotional irritability (GG = 1), one report of headache (GG = 1), two reports of acne (GG = 1; PLA = 1), and one report of chest pain (PLA = 1). The episode of chest pain was deemed unrelated to the study intervention  as this was in the placebo, and the participant was withdrawn from the trial and referred to their primary care physician. No serious adverse events occurred during the study.

Exploratory Analysis for Males

In a subgroup of males with a baseline total testosterone < 600 ng/dL (n = 8), no significant changes were observed in total testosterone (mean difference = −14.63 ng/dL, 95% CI: −59.97 to 30.72, P = .471) or free testosterone (mean difference = −0.18 pg/mL, 95% CI: −1.31 to 0.96, P = .727) during the placebo phase. Effect sizes for these placebo comparisons were small and non-significant (Cohen’s d = −0.27 for total testosterone; d = −0.13 for free testosterone), with 95% confidence intervals spanning zero, suggesting negligible differences (Table 8).

Table 8. Paired Samples t tests for Male Testosterone Outcomes (n = 8)

^aP < .05.

Abbreviations: P, placebo period; A, active supplementation period.

However, during the active supplementation phase, total testosterone showed a statistically significant increase (mean difference = 28.44 ng/dL, 95% CI: 7.45 to 49.43, P = .015). The corresponding effect size was large (Cohen’s d = 1.13), indicating a robust effect. In contrast, free testosterone did not differ significantly between active periods (mean difference = 0.80 pg/mL, 95% CI: −0.90 to 2.50, P = .303). Effect sizes were small to moderate (Cohen’s d = 0.39) (Table 8).

A post hoc power analysis was performed using G*Power (version 3.1.9.7) to assess the statistical power of the exploratory analysis. The test family was specified as
t tests, with the statistical test set to means: differences between two dependent means (matched pairs). Given the small sample size (n = 8), the observed effect size was large (Cohen’s d = 1.133).

Exploratory Analysis for Females

Paired samples t tests were also conducted in a subgroup of females with a baseline total testosterone < 32 ng/dL (n = 12) to examine within-subject changes in testosterone measures across placebo and active intervention phases. No statistically significant differences were observed for any of the paired comparisons (all P > .05).

For the placebo phase, total testosterone showed a non-significant decrease from baseline to follow-up (Mean difference = –1.43 ± 5.76, t(11) = –0.86, P = .407), and free testosterone remained unchanged (Mean difference = –0.03 ± 1.18, t(11) = –0.07, P = .943). Similarly, during the active phase (GG supplementation), no significant changes were observed. Total testosterone demonstrated a small, non-significant increase from baseline (Mean difference = 0.81 ± 7.10, t(11) = 0.39, P = .701), while free testosterone also showed no meaningful change (Mean difference = –0.01 ± 0.71, t(11) = –0.04, P = .968).

Discussion

The present study investigated the effects of GG supplementation on testosterone levels, CoQ10 levels, and validated patient-reported health outcomes in healthy middle-aged adults. No significant changes in testosterone or SHBG levels were observed between the GG and placebo phases across the full sample. Collectively, these results suggest that GG supplementation does not alter hormonal status in generally healthy populations with baseline values within normal physiological ranges.

Consistent with the recent clinical findings of Gheith et al. (2023),⁸ our trial demonstrated a significant increase in total testosterone among males with lower baseline testosterone (<600 ng/dL). The relatively large magnitude of this effect (Cohen’s d = 1.133, P = .015) indicates a potentially meaningful physiological response. This aligns with both preclinical studies showing that GG stimulates testosterone biosynthesis in Leydig cells through the 3’,5’-cyclic adenosine monophosphate (cAMP)/protein kinase (PKA)– steroidogenic acute regulatory protein (StAR) pathway,¹³ and with the subgroup analysis from Gheith et al., where males aged 30 to 49 with low baseline testosterone less than 700 ng/dL experienced significant increases in total, free, and bioavailable testosterone.⁸

In this study, total testosterone was measured using LC/MS-MS, whereas free testosterone was assessed using LabCorp’s direct analog immunoassay. While changes in total testosterone were observed, no parallel changes were detected in free testosterone. This difference may reflect methodological limitations of the direct free testosterone assay, which notably has lower sensitivity than equilibrium dialysis or calculated methods.¹⁸ Together, these data reinforce the potential of GG as a natural testosterone-supporting intervention, particularly in men with suboptimal baseline levels, linked to age-related declines or late-onset hypogonadism.¹⁹

The absence of an effect in women and in men with higher baseline testosterone may reflect a ceiling effect, whereby individuals with adequate endogenous production are less responsive to supplementation. This ceiling effect was observed in other testosterone-enhancing strategies, including dietary, botanical, and pharmacological interventions, where benefits are often confined to those with deficiency or insufficiency.²⁰

Another objective of this study was to investigate changes in CoQ10 levels. Although GG is an essential intermediate in the mevalonate pathway and supports the endogenous biosynthesis of CoQ10,²¹ GG supplementation in the current study did not result in a significant increase in CoQ10 levels. Several explanations may account for this observation. First, healthy individuals typically maintain adequate CoQ10 status, and CoQ10 biosynthesis is tightly regulated by feedback mechanisms that prevent excessive accumulation when physiological requirements are already met.²² Second, CoQ10 is primarily localized within mitochondria-rich tissues, and plasma concentrations may not adequately reflect tissue-specific or intracellular changes.^22,23 Third, GG serves as a substrate for multiple metabolic pathways, which may divert it from CoQ10 production.¹⁹

Despite the absence of significant increases, the crossover design revealed that CoQ10 concentrations declined significantly during the placebo phase but remained stable during GG supplementation. Since each participant served as their own control, this within-subject contrast strengthens the interpretation that GG may play a role in maintaining normal CoQ10 status. Preventing decline may be clinically relevant, particularly in populations where CoQ10 depletion is more likely, such as older adults, individuals with mitochondrial dysfunction, or patients undergoing statin therapy.²¹ Thus, while GG may not elevate CoQ10 concentrations in healthy, middle-aged individuals with adequate baseline status, its potential to preserve CoQ10 homeostasis under conditions of increased metabolic demand or pharmacologic inhibition warrants further investigation.

We also investigated the effects of GG supplementation on validated patient-reported outcomes of overall and sexual health. In this study, GG supplementation did not result in significant changes in self-reported physical, mental, or sexual health outcomes as assessed by the SF-12 and PROMIS SexFS v2.0 questionnaires. The absence of significant changes likely reflects the characteristics of the study population, which consisted of healthy, middle-aged adults without baseline sexual dysfunction or physical or mental health impairments.

Several strengths of this trial enhance confidence in these findings. The placebo-controlled crossover design allowed each participant to serve as their own control, thereby minimizing inter-individual variability and improving sensitivity to detect within-subject changes. Rigorous methodological controls, including standardized fasting and blood draw timing, further reduced potential confounding from diurnal hormone fluctuations. The use of once-daily 300 mg GG supplementation is more therapeutic, based on the recent dose-escalation trial.^8,13 The inclusion of both men and women between ages 40 and 65 years captured a population associated with age-related hormonal changes, while high supplement compliance without serious adverse events reinforced the feasibility and safety of GG supplementation in this demographic.

Several limitations are noted. The relatively small sample size, particularly in subgroup analyses, limits generalizability and statistical power. Also, the trial did not control for potential confounding variables such as dietary intake or physical activity, which may influence sex hormone dynamics. Compliance was assessed through self-reported diaries, with incomplete documentation and some adherence determined by verbal recall, introducing the potential for recall and social desirability bias.

Despite these limitations, the consistency between our results and Gheith et al. (2023) strengthens the evidence that GG is well-tolerated and beneficial in male populations with lower testosterone.⁸ Given the controversies surrounding testosterone replacement therapy and its associated risks,²⁴ GG may represent a promising natural alternative to support hormonal health in aging males.

Conclusion

In summary, this crossover trial supports the safety of GG supplementation and highlights its potential role in enhancing testosterone among men with suboptimal baseline levels. While no global effects were observed across the entire sample, the subgroup analysis provides rationale for future focused studies on GG as a novel nutraceutical strategy.

Although GG did not elevate circulating CoQ10 concentrations, its ability to prevent the decline observed in the placebo suggests a role in maintaining CoQ10 homeostasis. Together, these findings highlight GG supplementation as a promising nutraceutical strategy for aging men at risk of testosterone insufficiency and for middle-aged men and women to avert CoQ10 depletion.

These findings extend prior observations and highlight the potential of GG as a natural testosterone-supportive intervention in men with age-related declines. Further investigation in larger, targeted populations such as men with late-onset hypogonadism, men and women on statin therapy, or low blood CoQ10 levels is warranted to extend its clinical relevance.

Author Contributions

Conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft, preparation, writing—review and editing, visualization, and supervision, M.J., C.M, C.D.; project administration, M.J.; funding acquisition, M.J. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by Designs for Health, Inc, Palm Coast, FL, USA. There is no grant number to report.

Institutional Review Board Statement

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and approved by Pearl IRB (protocol #2024-0433, date of approval: 10 December 2024).

Informed Consent Statement

Informed consent was obtained from all participants involved in the study.

Data Availability Statement

Data are available upon reasonable request to the corresponding author.

Conflicts of Interest

Michael Jurgelewicz is employed by the study sponsor. Dr. D’Adamo is on the Scientific Advisory Board of Designs for Health, Inc. Interpretation of results and preparation of the manuscript were conducted collaboratively by all authors, including investigators not employed by the sponsor. The sponsor had no role in participant interactions, data collection, data curation, statistical analysis, interpretation of results, or the decision to publish the findings. No author received individual compensation from the sponsor. All other investigators are independent and not employed by the study sponsor.

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