Abstract
An increasing number of men are being diagnosed with hypogonadism. While many benefit from testosterone supplementation therapy, others who do not meet the criteria for hormone supplementation have turned to dietary adjuncts as a way or gaining improvements in libido, energy, and physical performance. These oral adjunct medications include controlled substances such as androstenedione, androstenediol as well as other “over-the-counter” options like DHEA (dehydroepiandrosterone) and herbal remedies like Tribulus terrestris. This review will focus on the use of these adjunct medications in isolation, or in combination with testosterone supplementation therapy as well as the biochemical nature of the supplements, the results of scientific trials as well as the side effects that limit their use. At the end of this review, physicians will have an improved understanding of the popular testosterone adjuncts being used currently as well as the availability of these substances and how they are used.
Introduction
The clinical diagnosis of hypogonadism is treated with a variety of testosterone supplementation therapies (TSTs). Along with this, while the amount of testosterone testing has decreased, the number of testosterone prescriptions has increased—suggesting the potential, and existence, of overuse (Layton et al., 2014). However, given the awareness of “low T” in popular culture, even men who do not have a formal diagnosis of hypogonadism (a combination of debilitating symptoms in the presence of low serum testosterone levels), are seeking ways in which to boost energy levels, libido, and improve muscle strength (Kovac, Rajanahally, et al., 2014). Indeed, many men who do not meet the threshold qualifications for TST have suggested that they may gain benefits through the use of oral “testosterone boosters” as dietary adjuncts (Genazzani et al., 2004; Jankowski et al., 2011). However, some studies report very few, if any benefits (Morales et al., 2009). Moreover, men on TST have also suggested that these adjunct medications could be used as a way of improving responses to TST but these findings are controversial (Basu et al., 2007; Farr, Banks, Uezu, Gaskin, & Morley, 2004).
The Food and Drug Administration (FDA) defines supplements as products that are not intended to treat, diagnose, prevent, or cure disease. Furthermore, these supplements cannot be a form of a current drug or synthetic equivalent. Indeed, some of the agents described within the current review are better classified as dietary adjuncts compared with dietary supplements. This particularly applies to androstenedione and androstenediol that, as a consequence of amendments to the Anabolic Steroid Control Act, are strictly available as controlled substances in the United States.
The origins of the legal aspects of these agents goes back to 1994 when the Dietary Supplement Health and Education act allowed for the marketing and sale of “natural” supplements that were not subject to regulation by the FDA. From there, it was not until 1996 that androstenedione and dehydroepiandrosterone (DHEA), two supplements marketed to boost testosterone levels, were approved as over-the-counter supplements. Two years later, famed baseball star, Mark McGwire openly admitted to use of androstenedione. This was followed by an astronomical 500% increase in sales of androstenedione (Smurawa & Congeni, 2007). In 2004, the U.S. Department of Health and Human Services, along with the FDA, began tightening the regulation of androstenedione—culminating in the passage of the Anabolic Steroid Control Act. This Act, which listed androstenedione as a schedule III controlled substance, instituted the rule that a physician prescription was required to obtain the medication. As such, consideration of these types of medications must be in the context of physician-prescribed adjunct medications as opposed to dietary supplements.
Currently there are three available forms of oral testosterone dietary adjuncts, or “boosters” that are available: androstenedione, androstenediol, and DHEA. While the former two are illegal without a physician’s prescription, the latter is still easily and legally obtained.
These adjuncts are targeted at men looking to boost energy and libido as well as wanting to increase physical performance and strength—whether they are on TST or not. In this article, the authors have reviewed the literature on the efficacy and safety of the most popular dietary testosterone boosters and adjuncts that are available.
Hypogonadism and TST
Hypogonadism is becoming an increasingly common medical issue among both young and older men (Coward et al., 2013). Recent trends have showed an increase in androgen use in men aged 40 years or older by more than threefold from 2001 to 2011 (Baillargeon, Urban, Ottenbacher, Pierson, & Goodwin, 2013). Furthermore, approximately 12% of all prescriptions were given to men younger than 40 years (Layton et al., 2014). Hypogonadism has also been linked to a number of various health conditions. Low serum levels of total testosterone, calculated free testosterone, and sex hormone binding globulin have been associated with an increased risk of developing metabolic syndrome and type 2 diabetes mellitus (even after adjustment for age, smoking status, alcohol consumption, socioeconomic status and level of physical activity; Kupelian et al., 2006; Laaksonen et al., 2004). The relationship of testosterone to diabetes and metabolic syndrome has not been studied in the context of dietary adjuncts, however, a recent review nicely captures the relationship as well as all the studies related to the topic (Kovac, Pastuszak, Lamb, & Lipshultz, 2014; Kovac, Scovell, Kim, & Lipshultz, 2014).
TST has also been linked to cardiovascular disease. Indeed, recent studies have examined the safety of TST and the relationship to cardiovascular disease (as reviewed in Scovell, Ramasamy, & Kovac, 2014) causing the FDA to revise testosterone indications and labels for testosterone medications within the United States. Specifically, articles by Finkle, Greenland, and Ridgeway (2014) and Vigen et al. (2013) have led many to preach caution when prescribing testosterone supplementation to elderly males. Briefly, Finkle and colleagues suggested that men older than 65 years had an increased risk of nonfatal myocardial infarctions within 90 days of TST initiation. In the latter article, elderly males with previous coronary angiography were examined and those men on TST had an absolute risk increase of 5.8% for cardiovascular events compared with those not receiving TST (Vigen et al., 2013).
Contrary to these findings however, low testosterone has been reported to be associated with increased mortality after adjusting for age, medical comorbidities, and other clinical covariates (Shores, Matsumoto, Sloan, & Kivlahan, 2006). As such, correction of low testosterone values yields a multitude of benefits along with high levels of patient satisfaction (Kovac, Rajanahally, et al., 2014; Smith et al., 2013).
The diagnosis of hypogonadism is made by a combination of lab values identifying decreased serum testosterone levels as well as symptoms and signs consistent with hypogonadism. These symptoms may include increased body fat, reduced muscle bulk and strength, decreased energy, mood, and libido, poor concentration and memory, and disturbances in sleep. The most frequently used laboratory test to confirm low levels of serum testosterone is the serum total testosterone, with normal values ranging from 300 to 1,000 ng/dL (Torre et al., 2006). However, the American Association of Clinical Endocrinologists Hypogonadism Task Force Guidelines report that symptoms of hypogonadism may manifest with normal serum total testosterone values, and recommend further tests such as morning serum total testosterone, free serum testosterone that is not bound to SHBG to further characterize levels of circulating testosterone (Torre et al., 2006).
Treatment of hypogonadism generally involves the use of TST to augment serum testosterone levels into a “normal” range. The most commonly prescribed forms of TST in the United States are transdermal gels. Other available options include intramuscular injections of short or long acting testosterone (i.e., enanthate/cypionate, undecanoate), transdermal patches, and pellet implants that all release testosterone directly into the bloodstream. Overall, the use of dietary adjuncts to boost testosterone levels remains low among physician prescriptions (Baillargeon et al., 2013). This is most likely due to a lack of familiarity among practicing physicians for their existence and doubts regarding their efficacy.
Androstenedione
From 1996 to 2004, androstenedione was available as an over-the-counter supplement. However, as mentioned above, in 2004 it was reclassified as an anabolic steroid and added to the list of controlled substances that require a physician prescription to obtain (Smurawa & Congeni, 2007). Androstenedione is an endogenous androgen that is synthesized in two different pathways (Figure 1). It is derived from the precursors pregnenolone and progesterone, both of which are originally synthesized from cholesterol. Androstenedione is then converted endogenously to testosterone by the action of 17-β-hydroxysteroid dehydrogenase. It can also be converted via aromatase to estrone, which is then transformed to other estrogens such as estradiol and estriol (Figure 1).
Steroid regulatory pathway.
Studies on the effects of androstenedione oral supplementation reported marked increases in serum levels at daily doses of 100 mg and 300 mg (Leder et al., 2000). A statistically significant, albeit modest, increase in serum total testosterone of ~16% to 34% from baseline occurred after 1 month of supplementation with daily 300 mg androstenedione (Leder et al., 2000). Daily supplementation with 100 mg of androstenedione, showed no significant increases in serum testosterone.
Long term, serum testosterone levels eventually returned to baseline pretreatment levels following 12 weeks of supplementation (Broeder et al., 2000). Of note, serum levels of estrone and estradiol were also significantly increased during administration of their precursor hormones (Broeder et al., 2000; King et al., 1999; Leder et al., 2000). These changes are not unexpected and likely due to the increased aromatization of both testosterone and androstenedione in the body combined with suppression of the hypothalamic–pituitary–gonadal axis, as was evidenced by attenuation of luteinizing hormone levels up to 33% in men on androstenedione (Broeder et al., 2000).
These physiological changes are important to note since increased levels of estrogens in men have been associated with postpubertal gynecomastia, increased body fat mass, unfavorable lipid profiles, and may potentially contribute to an increased risk of prostate cancer (Ismail & Barth, 2001; Tomaszewski et al., 2009; Treas, Tyagi, & Singh, 2013; Vermeulen, Kaufman, Goemaere, & van Pottelberg, 2002). Furthermore, recent research has suggested a role of estrogen in male libido (Ramasamy, Scovell, Kovac, & Lipshultz, 2014) further underscoring the importance of this hormone in male health. The relationship between testosterone and prostate cancer has also been discussed in depth recently (reviewed in Kovac, Pan, Lipshultz, & Lamb, 2014). The relationship between dietary adjuncts and prostate cancer, however, has never been examined, so caution should be maintained in using these adjuncts in men with prostate cancer.
With regard to clinical outcomes, patients undergoing resistance training and supplementation with oral androstenedione showed no increases in lean body mass, mean cross-sectional area of type-two muscle fibers as well as no decreases in fat mass versus placebo after 8 weeks of resistance training and 300 mg androstenedione supplementation (King et al., 1999). Additionally, patients receiving androstenedione supplementation were reported to have significantly lower HDL (high-density lipoprotein) levels and significantly increased LDL (low-density lipoprotein)/HDL and apolipoprotein A/apolipoprotein B ratios versus placebo (Broeder et al., 2000; King et al., 1999). All of which pose an increased risk for cardiovascular disease (Broeder et al., 2000; King et al., 1999). An additional side effect of androstenedione was suggested by a case report of a 29-year old male who developed impotence and oligospermia attributed to dietary supplementation of androstenedione (Ritter, Cryar, & Hermans, 2005). These findings were reversed 6 months following cessation of the supplement and a subsequent 3-month course of TST resolved his symptoms of low libido and energy (Ritter et al., 2005).
While randomized trials are lacking, the accumulation of available studies suggests that oral androstenedione supplementation results in modest and temporary increase in serum testosterone. Furthermore, it does so with very little to no anabolic/myotrophic effects. The resultant detrimental changes in blood lipid composition and potential increases in cardiovascular disease risk make appropriate follow-up in men using this adjunct very important (Table 1). Currently, the preponderance of the evidence suggests its use to be of minimal benefit in clinical application.
The primary roles and side effects of dietary testosterone adjuncts.
Note. DHEA = dehydroepiandrosterone; DHT = dihydrotestosterone; HDL = high-density lipoprotein; IIEF = international index of erectile function; LH = leutinizing hormone; LDL = low-density lipoprotein.
Androstenediol
Androstenediol is another endogenous androgen produced by modification of pregnenolone. It is derived from DHEA and can be converted to testosterone by the action of 3β-hydroxysteroid dehydrogenase (Figure 1). Following this, testosterone can then be converted to estradiol via the action of aromatase as previously described (Figure 1).
Oral supplementation of androstenediol has showed no statistically significant increases in area-under-the-curve concentrations of serum total and free testosterone 90 minutes after administration (Earnest, Olson, Broeder, Breuel, & Beckham, 2000). Interestingly, androstenediol produces a significant (103%-174%) increase in serum androstenedione levels after 90 minutes, indicating that there is likely an interconversion between androstenediol and androstenedione (Brown et al., 2001; Earnest et al., 2000). The increase in androstenedione levels and relative lack of significant increases in testosterone suggests that androstenediol is, in fact, preferentially converted to androstenedione rather than testosterone (Earnest et al., 2000). Possible mechanisms for this preference involve competitive enzyme binding reactions of 17β-hydroxysteroid dehydrogenase or feedback inhibition of the entire axis (Earnest et al., 2000; Figure 1).
Chronic, long-term supplementation of androstenediol appears to have effects on serum testosterone levels (Table 1). Indeed, after supplementation of an androstenediol-containing nutritional supplement for 28 days, statistically significant increases in serum androstenedione (174%), free testosterone (37%), and dihydrotestosterone (57%) were observed at the end of the study period (Brown et al., 2001). Interestingly, serum concentrations of total testosterone and prostate specific antigen were unchanged after 28 weeks of androstenediol supplementation (Brown et al., 2001). Similarl to androstenedione, supplementation with androstenediol increased the levels of serum estrogens (such as estrone and estradione), likely through the actions of aromatase (Brown et al., 2001). Androstenediol also negatively affected blood lipids in a similar fashion to androstenedione, decreasing HDL and increasing LDL—alterations that may contribute an increased risk of cardiovascular disease.
The predominant mechanism of action of androstenediol seems to be a conversion to androstenedione, as evidenced by the large increases in androstenedione during androstenediol supplementation (Brown et al., 2001; Earnest et al., 2000). This mechanism is consistent with results from studies looking at androstenediol supplementation. Furthermore, both androstenedione and androstenediol increase the level of estrone and estradiol in the body, likely due to the significant increase in levels of androstenedione, a substrate for the aromatase enzyme that converts it to the estrogens (Brown et al., 2001). Similarly, the side effect profile of androstenediol appears to be similar to that of androstenedione. In particular, the effects of both supplements on lipid levels are the same (decreased HDL and increased LDL) further supporting the presumption that androstenediol’s main effects are mediated via conversion to androstenedione. Currently, the preponderance of the evidence suggests its use to be of minimal benefit in clinical application.
Dehydroepiandrosterone (DHEA)
DHEA is an endogenous androgen that serves as the precursor to other prohormones such as androstenedione and androstenediol. Both of which are theoretically, in turn, converted to more potent androgens such as testosterone and dihydrotestosterone (Figure 1). Previous studies have suggested that DHEA has weak partial agonist activity at the androgen receptor (Chen et al., 2005). Furthermore, because of direct competition with testosterone for binding sites, it has been postulated that DHEA may serve as an antagonist at the androgen receptors (Chen et al., 2005). Currently, oral supplementation by DHEA remains unregulated by the FDA since it is not considered an anabolic steroid.
Studies have reported that oral supplementation of DHEA in older men (50 to 70 years old) produced significant dose-dependent increases in serum DHEA concentrations up to 300% to 400% of baseline (peaking between 1 and 8 hours after administration; Arlt et al., 1999). Interestingly, increases in serum DHEA levels were comparable to younger, 20-year old males suggesting no age limits to DHEA supplementation. Along with this, serum androstenedione concentrations were significantly increased and free testosterone concentrations exhibited a statistically significant increase to 113% of baseline with no significant changes in total testosterone or dihydrotestosterone concentrations (Arlt et al., 1999).
Similar to other prohormone supplements, serum estrogen concentrations increased significantly after DHEA supplementation. Estrone levels increased up to 226% of baseline and estriol up to 137% of baseline in a dose-dependent manner. In a more prolonged randomized doubly blind study of DHEA supplementation over 12 weeks, serum levels of DHEA showed significant increases from baseline, but no statistically significant changes in lean body mass, strength or serum testosterone levels were observed when compared with placebo (Wallace, Lim, Cutler, & Bucci, 1999).
A recent meta-analysis of all double-blinded, placebo-controlled randomized control trials involving oral DHEA supplementation confirmed that significant increases in serum DHEA and estradiol levels occurred after supplementation; however, no statistically significant increases in total serum testosterone concentrations were observed (Corona et al., 2013). Other factors that were also examined and reported to have no improvement following DHEA supplementation included lumbar or femoral neck bone mineral density and sexual function outcomes (international index of erectile function [IIEF-15]; Corona et al., 2013). DHEA supplementation has also been associated with an overall reduction of fat mass using dual-energy X-ray absorptiometry scans. A multivariate regression model identified no correlation between fat mass reduction and DHEA (Corona et al., 2013). This effect has been attributed to the conversion of DHEA to estrogens and androgens, which seem to have much more significant effects on body fat mass.
Other Supplements
A number of herbal oral supplements have been marketed to boost testosterone levels, increase energy, and improve symptoms associated with hypogonadism. Often these herbal extracts are found combined with the prohormones detailed above and include compounds such as Tribulus terrestris, Tinospora cordifolia, and icariin.
Tribulus terrestris is a flowering plant found in tropical and temperate zones throughout the world and has been used in various traditional medical practices in various cultures. A systematic review of the effects of this herb suggest that while the supplement may have some ability to increase serum testosterone in animals, studies in humans identify increased serum testosterone only when used in conjunction with other supplements (Qureshi, Naughton, & Petroczi, 2014).
Tinospora cordifolia is another commonly taken herbal supplement meant to increase testosterone levels. It is a vine native to tropical areas such as India, Myanmar, and Sri Lanka. No extensive human trials have been completed to this date, but supplementation with Tinospora cordifolia in Muzzafarnagari rams showed no significant effects on serum testosterone or physiological and morphological biochemical attributes of semen (Jayaganthan et al., 2013).
Icariin, also known as horny goat weed extract, is derived from plants of the Epimedium genus and possesses known PDE5 inhibitor–like effects (Ning et al., 2006). No human trials have been completed at this time, but low doses of icariin in rats showed significantly higher intracavernosal pressure to mean arterial pressure ratio as well as mean arterial pressure when compared with controls (Shindel et al., 2010). The rats also showed greater positive staining for neuronal nitric oxide synthase and calponin in penile tissue suggesting that icariin may be a potentially useful option for treating erectile dysfunction in humans. Without further studies in humans however, the effects of icariin on erectile dysfunction cannot be fully determined.
VigRX Plus, a multiherbal oral supplement purported to relieve erectile dysfunction showed promising results in a recent study published in the BMC journal of Complementary Alternative Medicine (Shah et al., 2012). VigRX Plus consists of a mixture of Panax ginseng, Serenoa repens, Gingko biloba, Crataegus laevigate, Ptychopetalum olacoides, Erythroxylum catuaba, Cuscuta chinensis, and Epimedium sagittatum extract. In this randomized, double blind study, men aged 25 to 50 years were randomized to receive two doses of VigRX Plus or placebo for 12 weeks (Shah et al., 2012). Results identified that while there was no difference in serum testosterone levels between the treatment and placebo groups, the mean IIEF scores increased significantly (9 vs. 0.6 points with placebo) at the end of the study (Shah et al., 2012). Assessment of satisfaction with the supplement identified that 90% of patients reported a desire to continue the supplement versus 3% in the placebo group (Shah et al., 2012). Furthermore, the supplement was tolerated well with no significant adverse effects reported and the most common adverse effect reported being mild fever.
Side Effects of Dietary Adjuncts
Prohormones can drastically alter the normal physiologic response of the various endocrine axes and alter serum hormone concentrations in the body. Increased androstenedione in rats is associated with enlargement of brain areas associated with aggression (Broeder et al., 2000; Tomaszewski et al., 2009). An unanticipated side effect of prohormone supplementation in men is the detrimental effect on lipid profiles associated with androstenedione and androstenediol supplementation and increased serum estrogens (Broeder et al., 2000; Tomaszewski et al., 2009). Decreased HDL cholesterol represented a significant increase in the risk of cardiovascular disease and was a component of the Framingham coronary heart disease risk score. Increased serum androstenedione also appeared to increase the aromatase-mediated conversion of androstenedione to estrogens such as estrone and estradiol. It appears that these estrogens have an inhibitory effect on the hypogonadal–pituitary–gonadal axis, which in turn suppresses luteinizing hormone and follicle-stimulating hormone secretion, leading to further decreases in testosterone production.
In addition, increased levels of testosterone and estradione due to increased androstenedione can also lead to gynecomastia in males (Berkovitz, Guerami, Brown, MacDonald, & Migeon, 1985). Recent data suggest that chronically increased levels of circulating estrogens stimulate growth and transformation of prostate epithelial cells, imparting an increased risk of developing prostate cancer (Treas et al., 2013). These supplements can also affect other organ systems such as the liver. There has been one recent case report of a man who developed drug-induced liver injury caused by ingestion of a prohormone supplement called Post Cycle II, which according to the manufacturer is a blend of Tribulus terrestris, icariin, and aromatase modulators zinc monomethionine aspartate, Agaricus bisporus extract, trans-resveratrol, and 7-methoxyflavone (Hoedebecke, Rerucha, Maxwell, & Butler, 2013).
FDA and Dietary Supplements/Adjuncts
When discussing adverse effects of oral supplements and adjuncts, it is important to keep in mind that nutritional substances are not subject to the rigorous safety and efficacy standards that the FDA imposes on medications. The FDA’s role in regulation of nutritional supplements is set by the Dietary Supplement Health and Education Act of 1994, which not only provides the definition of what a dietary supplement is but also the part responsible for safety and regulation. The act states that the manufacturer is responsible for not only listing the ingredients of the supplement on the packaging but also ensuring the safety of those ingredients before the supplement is marketed. New products are required to undergo a premarket review for safety and efficacy data, but the manufacturer conducts this review and the data garnered from this review regarding safety and efficacy is not required to be submitted to the FDA or any other regulatory agency.
Claims and statements of quality insurance found on the packaging are also subject to the discretion of the manufacturer. There is no regulatory agency that confirms the accuracy of the information found on the labels, including claims of quality, effectiveness, or ingredients. Without outside quality control, dietary supplements may contain contaminants or varying levels of the ingredients claimed to be present in the supplement. Investigation of complaints regarding supplement use by the FDA almost necessitates a rampant public calamity, and can only restrict a dietary supplement from the market if the supplement is demonstrated to be unsafe. Taken in total, these statements conclude that it is the responsibility of the manufacturers to ensure that their product is effective or safe for human consumption.
Conclusions
With current literature documenting the various detrimental health effects of hypogonadism such as diabetes, metabolic syndrome, and mortality, the incidence of testosterone supplementation is gradually increasing. More men are turning to oral prohormone supplements and dietary adjuncts to improve muscle mass and appearance or combat the decreased energy, libido associated with hypogonadism and low testosterone.
The most commonly used prohormones used in these dietary adjuncts include androstenedione, androstenediol, and DHEA. Studies have reported that the effects of these prohormones are unpredictable and dose-dependent, with no reliable significant improvement in symptoms or objective measure of serum free and total testosterone. Furthermore, the regulations now imposed on several of these agents make them difficult to obtain legally. Other herbal extracts claiming to boost testosterone such as Tribulus terrestris, Tinospora cordifolia, and icariin are also commonly found in these supplements. While results of studies on icariin report potential benefits as a supplemental agent to be used to manage hypogonadal symptoms, Tribulus terrestris and Tinospora cordifolia extracts show no demonstrable effects on serum testosterone.
Adverse effects can include not only suppression of luteinizing hormone and follicle-stimulating hormone leading to impaired fertility and decreased production of endogenous testosterone but also increases in circulating estrogens due to the conversion of prohormones and testosterone to estrogens via aromatase. Additional adverse effects of dietary adjuncts may be caused by the lack of regulation of safety and efficacy by the FDA (particularly for DHEA since androstenedione and androstenediol are now controlled substances). In conclusion, effective and safe forms of treatment for hypogonadism are available, but should be used with caution and under the supervision of a physician. Furthermore, more studies are required examining the benefits of dietary adjuncts in hypogonadal men on TST.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.