Plasticized - Put Up or Shut Up: How Toxic is Our Daily Load of Bisphenol A and What are the Main Routes of Exposure?

"BPA free" labels may help to sell products. With more and more of the replacements being identified as just as, sometimes more hazardous than the original, they are, however, by no means as safe as the average consumer is made to believe by the industry.

I have been keepin' you up-to-date on the latest research on bisphenol A and often not less toxic alternatives in the Facebook news (if you didn't do that already, like facebook.com/SuppVersity to see them in your newsfeed). The publication of a new review by scientists from the West Pomeranian University of Technology in Szczecin in Poland reminded me that it may be worth addressing this ubiquitous hormonal disrupter in a detailed article again.

As Tomza-Marciniak et al. point out as early as in the first sentence of the abstract to their review (which had been published ahead of print in June and was now officially published in the Journal of Applied Toxicology), "bisphenol A (BPA) is characterized by a pronounced influence on human hormonal regulation" (Tomza-Marciniak 2017).

You can find more True or False articles at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

You Can Drum Yourself Lean

You Can Wash Pesticides Away

Milk = Poisonous Hormone Cocktail

The aim of the scientists' latest work "was to collect and summarize data on the influence of BPA exposure on reproductive health" (Tomza-Marciniak 2017). An undertaking that yielded quite disconcerting results, namely:

• strong proof confirming that BPA is an ovarian, uterine and prostate toxicant at a level below the lowest observed adverse effect level (50 mg/kg body weight) as well as a level below the proposed safe level (4 μg kg−1 bodyweight);
• reliable evidence in relation to the negative effect of BPA on sperm quality and motility;
• limited evidence pertaining to the case of the potential of BPA to affect polycystic ovary syndrome occurrence

What makes this review particularly useful are the illustrations of the proven and suspected (side) effects on sex hormones, fertility, etc. - figures like Figure 1 and Figure 2.

Figure 1: Effect of BPA on female reproductive processes. BPA, bisphenol A (Tomza-Marciniak 2017).

Figures that leave little doubt that fish and frogs which live in "plastic intoxicated" environments are by no means the only victims of environmental BPA exposure.

Figure 2: Effect of BPA on male reproductive processes. BPA, bisphenol A (Tomza-Marciniak 2017).

In fact, convincing evidence exists that BPA could be one of the factors that are promoting the increase in the number of couples who are willing, but unable to conceive. Epidemiological studies, for example, found statistically highly significant correlations between sexual function and the concentration of BPA in almost 500 male subjects. More specifically, Li et al. observed significant (P < 0.001) decreases of libido, erection problems and a lower ejaculation intensity with increased levels of urinary BPA in 2010 and a 3.4-fold increased risk of having a critically low sperm count, a 3.3-fold increase of low sperm vitality, a 4.1-fold increased risk of low sperm counts and a 2.3-fold increased risk of low sperm motility. Moreover, the Polish scientists report that...

"[n]egative effects of BPA on the reproductive abilities of men were obtained in a cross-sectional study by Liu et al. (2015) on 592 men from China stated that a high exposure to BPA is related to a significantly increased concentration of prolactin (P < 0.001) and sex steroid binding globulin (P < 0.001) and to a reduced androstenedione level (P < 0.001) in blood and free androgen index (P = 0.021) and in this way may contribute to male infertility" (Tomza-Marciniak 2017). 

Next to a potential direct toxic effect on the testes and/or sperm, its ill effects on hormonal health are thus probably the cornerstone of BPAs anti-fertility + anti-virility effects - with corresponding side effects having been observed in females.

Migration levels of bisphenol A from 12 polycarbonate baby bottles according to the days of use (Brede 2003).

How to limit your BPA exposure: As previously highlighted, our exposure to BPA starts at the very moment we're conceived and thus significantly before we're born (Ikezuki 2002). It is thus of particular importance for mothers-to-be to avoid all of the sources of BPA - sources which include foods from cans with epoxy resin linings, drinking water, air and even dust.

Ever since the 1990s, we've known that BPA leaches from plastic bottles - including, baby bottles. In that, the leaching has been found to be present even in brand new bottles (Vandenberg 2007).

As Brede et al. (2003) found out the leaching of BPA into whatever you store in these plastic containers will significantly increase whence they've been in a dishwashing machine, in/exposed to boiling water or brushed to scrub them clean. Using plastic containers to heat food (in the microwave or elsewhere) should be a no-go, the use of PVC stretch films to wrap foods has been associated with food contaminations ranging from 43 to 483 mg/kg - with fatty products, like olive oil, being even more susceptible to the effect than acidic ones.

And the former are only the most obvious routes of exposure. Sign. amounts of BPA have also been found in various other consumer goods from paper towels made from recycled paper (0.55-24.1 mg/kg), food containers made from both recycled paper (0.19-26 mg/kg | lower levels in virgin paper). Then, there's the better-known exposure from metallic food cans which are protected from rusting and corrosion by the application of epoxy resins as inner coatings that is quantified at 4-23 microgram of BPA per can and 1.7-fold to 55.4-fold increases of the original concentration of BPA when the cans were heated (100°C).

Few of us will be aware, though, that we don't even have to eat something to be exposed to the hazardous plastics. As Tomza-Marciniak et al. point out "[s]everal resin-based monomers are used in dentistry as preventative sealants, adhesives, and restorative materials" - for example, since the 1960’s, BPA diglycidyl methacrylate has been used as a component of many dental restorative materials. And while 60-80% of these monomers are typically polymerized in situ small quantities of unreacted monomers have been shown to leach from polymerized dental materials.

What's even more alarming, though, is that German studies indicate that our drinking water is increasingly polluted with BPA. With twenty percent of the samples, Kuch & Ballschmiter collected in 2001 containing detectable levels of BPA (LOD: 11 ng/L) and nine locations presenting with levels over 100 ng/L, that alone wouldn't be a problem. The observation does, however, add to the evidence of the ubiquitousness of BPA in our environment. In fact, significantly higher concentrations have been found in the waters of 30 US rivers that have been tested for their BPA content and showed levels ranging from 0.14 micrograms per liter to a maximum measure of 12 micrograms per liter. Even breathing can be a problem today: In a survey of 120 homes for the presence of endocrine disrupting chemicals, Rudel et al. found BPA present in 86% of house dust samples at concentrations ranging from 0.2-17.6 micrograms/gram of dust. So what? Stop breathing? The problem is that you may still absorb BPA from the various cosmetics that are either packaged in BPA-containing bottles or contain it as a stabilizer and/or antioxidant (Demierre 2012).

To avoid BPA exposure altogether does thus seem impossible, what is possible, however, is to not use re-usable plastic containers or throw-away plastic films - specifically not for heating or storing fatty or acidic foods; as well as to be skeptical about the alleged superiority of "BPA-free" products that may not contain BPA but alternatives like BPS of which we already know that they are at least as problematic as the original (Hill 2017).

Interestingly enough, other studies, like Goldstone et al. (2015) "did not show any evidence that BPA decreased semen quality" in men. With Mendiola et al. (2010) reporting no significant associations between any of the semen parameters and urinary BPA concentration, in a cross-sectional study, examining a group of 375 men confirming the fertility-related observations of Goldstone et al. but highlighting that there is a ...

"significant inverse association between urinary BPA concentration and free androgen index (β = −0.01, 95% CI: –0.09, −0.004) and the free androgen index/luteinizing hormone ratio (β = −0.11, 95% CI: 0.18, −0.03) as well as a significant positive association between BPA and sex hormone-binding globulin (β = 0.07, 95% CI: 0.007, 0.13)" (Tomza-Marciniak 2017)

Moreover, it seems that evaluations of BPA exposure using urine or blood should also consider using semen. It appears that although the content of different xenobiotics including BPA in semen can reflect the content in blood, the results of statistical analyses are not always similar.

Figure 3: Hyperprolactinemia (=elevated levels of prolactin) are only the most significant hormonal side effect of BPA exposure in men Liu et al. observed in their 2015 paper in Environmental Toxicology and Pharmacology.

For instance, Vitku et al. (2016) have found that BPA levels in blood plasma were positively correlated (P < 0.001) with BPA levels in semen, yet only seminal BPA, not plasma BPA, was negatively associated with different parameters of semen, such as sperm concentration (r = −0.198; P = 0.009), sperm count (r = −0.178; P = 0.018) and morphology (r = −0.160; P = 0.044).

We know very little about the real-world effects of BPA on women

In the understandable absence of obviously unethical controlled long-term studies on women (including pregnant women), we will once again have to focus on epidemiological data, here. Said studies have shown quite consistently that ...

• BPA disturbs hormonal regulation and contributes to infertility in women - with infertile women being reported to have 2x higher BPA levels than fertile controls 
• there is a significant association between BPA levels in the blood and the risk of infertility (+730%! La Rocca 2014) in otherwise healthy women - especially in metropolitan areas
• elevated BPA levels are associated with endometriosis (although not in all studies) and polycystic ovary syndrome aka PCOS (in almost all studies).

I guess you will now think: "Well, all that is not news!" - and in fact, you're right. What is "news" or at least worth revisiting is the increasingly convincing evidence that ...

...the officially proposed safe level (4 μg/kg bodyweight | EFSA 2015) of exposure may enough to trigger hormonal and non-hormonal side effects!

What's making things worse is that BPA, which will directly bind to human estrogen and androgen receptors is by far not the only hormonal disruptor we are exposed to on a daily basis (Wetherill,  2007; Viñas 2012). Against that background, it is only a semi-relevant argument that ...
"a large number of experimental studies are performed at high doses, levels not occurring in daily life, or are carried in in vitro conditions, causing a possible inadequacy to a real risk of human BPA exposure" (Tomza-Marciniak 2017).

In fact, both men and women are subjected (practically from the moment of conception) to “cocktail” of compounds, such as BPA, which have a relatively high toxicity threshold only when assessed in isolation, but unknown and difficult to quantify effects on reproductive health when they are administered together. It is thus, as Tomza-Marciniak et al. point out imperative that future studies assess the "effects of a combined activity of a few toxicants that chronically act on humans" (Tomza-Marciniak 2017). As of now, all we have are a bunch of animal studies using combinations such as additive (negative) health effects of nonylphenol and bisphenol A in swordfish (Kwak 2001), or cell line studies that show how BPA and titanium-dioxide, commonly found in food and cosmetics exert synergistic effects (Zheng 2012), too. If you want to learn more about this issue in general, you may want to read the review by Carpenter et al. (2003 | free FT).

In view of the fact that the said allegedly "safe level of BPA" is probably everything but safe (esp. w/ the co-exposure to other xenoestrogenic plasticizers), I suspect that the website of the Polycarbonate/BPA Global Group which represents the leading global manufacturers of bisphenol A (BPA) and polycarbonate plastic is not going to soothe you.

What's the verdict, then? Even though there's an (urgent) need for studies investigating the joint effect of exposure to multiple toxicants, there's "strong evidence that BPA is a toxicant (ovarian, uterine and prostate) at a level below the lowest observed adverse effect level (50 mg/kg bw) as well as a level below the proposed safe level (4 μg/kg bw)" (Tomza-Marciniak 2017).

The answer to the question of whether we achieve these concentrations, or not, depends on whom you're asking. While the European Union claims that the BPA exposure of its average citizen ranges from 0.48 ot 1.6 µg/kg body weight/day, New Zealanders are supposedly exposed to much higher doses of 4.8 µg/kg body weight/day - an amount that is slightly above the "proposed safe level", of which you've already heard that many scientists believe that it is not safe, anyways; and beyond good and evil for babies, for whom scientists estimate the exposure per kg body weight at whopping 24.14 µg/kg body weight/day for new-borns and 15 µg/kg for three months olds!

Speaking of safety. Little doubt exists about the experimentally and epidemiological confirmed toxic effects on the prostate gland, sperm (quality and motility) and fertility. However, "[l]imited evidence" is available of the ability of BPA to cause PCOS, while "no clear consistent results" from either epidemiological or animal model studies exist with respect to: (1) the evaluation of associations between BPA and implantation failure in women; (2) evaluation of associations between BPA and sexual dysfunction in men; and (3) impact of BPA on birth rate, birth weight and length of gestation in human beings | Comment on Facebook!

References:

• Brede, C., et al. "Increased migration levels of bisphenol A from polycarbonate baby bottles after dishwashing, boiling and brushing." Food Additives & Contaminants 20.7 (2003): 684-689.
• Carpenter, David O., Kathleen Arcaro, and David C. Spink. "Understanding the human health effects of chemical mixtures." Environmental Health Perspectives 110.Suppl 1 (2002): 25.
• Demierre, Anne-Laure, et al. "Dermal penetration of bisphenol A in human skin contributes marginally to total exposure." Toxicology letters 213.3 (2012): 305-308.
• Ikezuki, Yumiko, et al. "Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure." Human reproduction 17.11 (2002): 2839-2841.
• Kuch, Holger M., and Karlheinz Ballschmiter. "Determination of endocrine-disrupting phenolic compounds and estrogens in surface and drinking water by HRGC−(NCI)− MS in the picogram per liter range." Environmental science & technology 35.15 (2001): 3201-3206.
• La Rocca, Cinzia, et al. "Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas." International journal of environmental research and public health 11.10 (2014): 10146-10164.
• Kwak, Hyeong‐Il, et al. "Effects of nonylphenol, bisphenol A, and their mixture on the viviparous swordtail fish (Xiphophorus helleri)." Environmental toxicology and chemistry 20.4 (2001): 787-795.
• Li, De‐Kun, et al. "Relationship Between Urine Bisphenol‐A Level and Declining Male Sexual Function." Journal of andrology 31.5 (2010): 500-506.
• Liu, Xiaoqin, et al. "Exposure to bisphenol-A and reproductive hormones among male adults." Environmental toxicology and pharmacology 39.2 (2015): 934-941.
• Tomza‐Marciniak, Agnieszka, et al. "Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies." Journal of Applied Toxicology (2017).
• Vandenberg, Laura N., et al. "Human exposure to bisphenol A (BPA)." Reproductive toxicology 24.2 (2007): 139-177.
• Viñas, René, Yow-Jiun Jeng, and Cheryl S. Watson. "Non-genomic effects of xenoestrogen mixtures." International journal of environmental research and public health 9.8 (2012): 2694-2714.
• Wetherill, Yelena B., et al. "In vitro molecular mechanisms of bisphenol A action." Reproductive toxicology 24.2 (2007): 178-198.
• Zheng, Dan, et al. "Effects of the interaction of TiO 2 nanoparticles with bisphenol A on their physicochemical properties and in vitro toxicity." Journal of hazardous materials 199 (2012): 426-432.

Men Are Not Always Thinking About Sex. Study Says: There Are At Least 4 "Good" Reasons They Don't - Stress Is #1! Plus: A Proven De-Stress Protocol to Restore Your Libido

If either of these individuals remind you of yourself, you should reduce his stress levels.

Recent research suggest: The good old saying that "Men always think about sex!" is essentially untrue (The "!" indicates that I used the feminist version of this common "wisdom").

If we put faith in the results of a recent European study from the Department of Clinical Psychology at the Instituto Universitário in Lisbon, Portugal, the Department of Psychology at the University of Tromsø in Tromsø, Norway, and the Sexology Unit at the Faculty of Humanities and Social Sciences, University of Zagreb, Croatia, stress is the common denominator that distracts men from their original duty to do what has to be done for the survival of the human race ;-)

Homo coitum quaerens aut evitarens?

It may sound surprising, but unlike sexual function, the sexual desire of the male members of the human race has not been examined as extensively as the one of their female counterparts. When you think about the initially quoted "wisdom", it is actually not that surprising.  Men are are after all believed to be always looking for the next "catch".

The problem cannot be that prevalent, can it? Yes it can! According to recent data from the The National Health and Social Life Survey (NHSLS), the average American's prevalence of “lacking desire for sex” ranged from 14% (for those 18–29 years old) to 17% (for those 50–59 years old). In spite of the fact that the exact figures are debatable, the currently available literature supports the notion that 15-20% of the US men 'don't think about sex at all'. If we take a look at international data the figures don't look better: Depending on the geographic region 13% to 28% of the ~14,000 men aged 40–80 years from 29 countries in the Global Study of Sexual Attitudes and Behaviours said that their sexual desire had been low for at least 2 months Laumann. 2005).

After focusing more or less exclusively on functional aspects of male sexuality for decades, research does now start to draw and embrace a more versatile image of male and general human sexuality. According to studies by Hyde and Janssen, the black-and-white gender differences which is also at the heard of the saying "men think about sex all day" is in fact non-existent. On the contrary, gender theorists have recently suggested that greater diversity exists within gender than between gender (Hyde. 2005+2007; Janssen. 2008).

Sexual disinterest is stressful!

Faced with the surprisingly high rates of sexual disinterest in men, scientists like Mccarthy et al. have already identified several major relationship problems as potential culprits. In view of what you've learned already, it should be obvious that these problems are not necessarily related to the 'classic' mismatch in sexual interests between a hyperactive male and an (under-)active female partner. On the contrary, the data in Figure 1 makes it plain obvious that for men in their thirties, it would not be unlikely that they are disinterested and their wives or girlfriends dissatisfied.

It goes without saying that problems like these and the mismatch between the perceived and the expected level of sexual desire are stressing - very stressing, according to the data Ana Carvalheira's, Bente Træen's and Aleksandar Štulhofer gathered in inteviews with heterosexual men from Portugal, Croatia, and Norway (Carcalheira. 2013):

Figure 1:Lack of desire and professional stress, two sides of the same coin? Data based on Carcalheira (2013)

In the worst case scenario a man will get caught in a vicious circle of professional stress ⇆ lack of sexual desire ⇆ private stress that is hard to break. Against that background it's only logical that the essence of the recommendations in the bottom line of this article is to get rid of the stress that's keeping you from thinking about sex.

"Stress ⇆ Sexual Disinterest" - it's that easy!

A 2013 study by Talbott et al. suggests that Tongkat Ali, a traditional testosterone and libido booster works mainly be reducing stress levels (learn more)

If you don't believe in the deeper truth of this 'equation', I suggest you go back to an article I wrote earlier this year (see Beyond Testosterone: 200mg/day of Tongkat Ali (Eurycoma Longifolia) for Stress Management & Improved Mood!?" | read more). It deals with a traditional "testosterone booster" and its effects on stressed individuals... you will see: Stress is not only a libido-, it's also a testosterone -killer (no surprise, right?).

It is thus not really surprising that the data from the Carcalheira study tells us that men who feel distressed about their own lack of libido were 2.5x more likely to suffer from anxiety right before sex  and/or have trouble maintaining an erection.

To be stressed or not to be stressed - that's the question!

Just as the cliche would have it, the highly reserved Norwegians were 3x more likely than the red-blooded self-proclaimed Latin lovers from Portugal to suffer from a lack of sexual desire. With a 50% higher risk of losing interest in the other sex, the participants from Croatia end up somewhere in between the 'Latin lovers' and the 'prudish Vikings'.

Table 1: Sociodemographic characteristics, individual variables, and relationship-related characteristics as correlates of a distressing lack of sexual interest among healthy heterosexual men who are not using antidepressants (Carcalheira. 2013)

Aside from their origin there were other sociodemographic characteristics, individual variables, and relationship-related characteristics which were found to be associated with the an increased risk of suffering from a lack of sexual desire. As the data in Table 1 goes to show you, having children, even young ones, was, contrary to what you may have expected, not among these characteristics. In contrast to the self-confidence on erectile function, of course.

What's I personally find quite telling is the high rate of a distressing lack of sexual desire in long-term (5years +) relationships and as a consequence of an indifferent attitude towards the attractiveness of the sexual partner. Interestingly, finding your wife or girlfriend "neither attractive, nor unattractive" is an even greater turn down than thinking of her as a "very unattractive" (see Table 1).

"And that's all stress?"

No, that's not all stress... In the previous paragraph we have already learned about a libido killer that cannot be traced back to stress: The lack of 'adventure', 'novelty' or whatever you may call it - a phenomenon which is probably also the reason that people start looking at their partner as "neither attractive nor unattractive" is another important contributor to sexual disinterested in men. One out of 22 if you will - 22 items on the scientists list of potential causes of a reduced sexual interest:

Table 2: Self-assessed causes of a reduced sexual interest during the past 6 months among heterosexual Portuguese, Croatian, and Norwegian men in percent (Carvalheira. 2013)

I know, not all of them appear logical. Why would masturbating too often be associated with a reduced interest in sex? ⇦ That does not sound right - right? Something similar can be said for the Croatian porn fans (22.5%). In the end, though, it does not change the overall picture: It is stress that's gnawing at our sexual desire, guys.

The Dimou protocol: Diaphragmatic breathing is performed by taking deep diaphragmatic inspirations followed by slow prolonged expirations.  In the second phase of PMR relaxation, patients were guided through successive contractions and relaxations of different large muscle groups in a down-top orientation. The process was complemented by guided imagery involving mental exercises, designed to allow the mind to influence the health and well-being of the body (GI is used with standard medical treatment in people with cancer and other diseases, such as fibromyalgia, as it can help to reduce stress, depression and manage pain). In each step, the patients were encouraged to focus on the difference between tension and relaxation, thus gradually sharpening the perception of the relaxation response.

What So what can be done? By now the question "what can be done" should - at least on the surface level - already have a rhetorical character. It's obvious that you have to de-stress. The only question is: How do you do that? Luckily (for us), P.A. Dimou et al. have just successfully tested an anti-stress program that consisted of progressive muscular relaxation (PMR), diaphragmatic breathing and guided imagery and was topped off with a handful of tips to achieve better time management. The program was designed to optimize sexual health in young men and it worked! It worked like a charm: Over the course of the 8-week stress management program practicing the PMR + diaphragmatic breathing + guided imagery regime twice a day effectively reduced the number of men who were totally or somehow dissatisfied with their sex life decreased from 9 to 4 (-55%; cf. Dimou. 2013). Aside from the intended benefits in sexual satisfaction, the young 60 young men in the active arm of the Dimou study also lost weight (-3% BMI), felt less overall less stressed (-23%; social stress subscale -11%) and achieved +6% higher scores in the general health evaluation.

PMR and guided imagery does not sound like you? Well, I guess simply limiting your mobile phone, email, Facebook and SMS use, making room for the occasional time out with a cup of tea during the working hours, a rigorous 7h+ sleeping regimen and letting go of the 'more is more principle' will work wonders even in the absence of 'meditative' interventions....ah, and don't forget: Don't stress about de-stressing that would ruin all your efforts to find inner peace ;-)

Reference:

• Carvalheira A, Træen B, Štulhofer A. Correlates of Men’s Sexual Interest: A Cross-Cultural Study. J Sex Med. 2013 [accepted manuscript]
• Dimou PA, Bacopoulou F, Darviri C, Chrousos GP. Stress management and sexual health of young adults: a pilot randomised controlled trial. Andrologia2013,xx, 1–10 [accepted manuscript]
• Hyde JS. The gender similarities hypothesis. Am Psychol 2005;60:581–92.
• Hyde JS. New directions in the study of gender similarities and differences. Curr Dir Psychol Sci 2007;16:259–63.
• Janssen E, McBride K, Yarber W, Hill B, Butler S. Factors that influence sexual arousal in men: A focus group study. Arch Sex Behav 2008;37:252–65.
• Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E, Wang T; GSSAB Investigators’ Group. Sexual problems among women and men aged 40–80 y: Prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res 2005;17:39–57
• Mccarthy B, McDonald D. Sex therapy failures: A crucial, yet ignored, issue. J Sex Marital Ther 2009;35:320–9.

40% Increase in Total + 50% Increase in Free Testosterone - Two Not Necessarily Undesirable Side Effects of Sildenafil. Human Study Confirms Direct Effect of PDE-5 Inhibition

Either you buy one of the bazillion OTC test-boosters that will not do anything for your testosterone levels, but may have minimal effects on your libido; or, you get a script for the blue pills and accept that one of the side-effects of these proven libido-boosters is an increase in testicular testosterone production.

If you were all Germans, I would probably be cracking a joke about the lead author's name "Spitzer", but in view of the fact that you aren't and that it would be a saucy one I will stick to the news-piece alone - it's saucy enough, anyways ;-)

Actually you've heard Carl and me talk about the purported testosterone boosting effects of sildenafil aka Viagra on the Science Round Up in the past, but Mr. Spitzer and his colleagues from the Greenfield Health Center are the first to prove the potency of the testosterone response in male subjects who received "an optimized dose" (more on that later) of sildenafil, as well as its "direct action on the testes" in a controlled larger-scale trial (Spitzer. 2013).

More than just "spitz" (engl. "horny")

The data Matthew Spitzer et al. analyzed came from the Testosterone and Erectile Dysfunction Trial in the course of which 140 men, aged 40–70 years with erectile dysfunction, low serum total testosterone (<11.4 nmol/L; 330 ng/dL) and/or free testosterone (<173 pmol/L; 50 pg/mL) over received starting doses of

• 25mg sildenafil, if they were on an alpha-blocker
• 50mg sildenafil, if they never used sildenafil before, and
• 100mg sildenafil, if they were viagra veterans

for  3–7 weeks. The men in the 25mg and 50mg groups had the chance to increase the dosage to up to 100mg "on occasion"; or, in other words, when their sexual desire did not match their physical function.

Figure 1: Changes of testosterone and other hormones rel. to baseline level (Spitzer. 2013)

As you can see in Figure 1 the ingestion of a handful of the infamous blue pills lead to significant increases of in total (+3.6 nmol/L = 103 ng/dL; p<0.001) and free (+110 pmol/L = 31.7 pg/mL; p<0.001) testosterone levels and were accompanied by parallel increases in serum DHT (0.17 nmol/L = 4.9 ng/dL; p<0.001) and oestradiol (14 pmol/L = 3.7 pg/mL; p<0.001) and significant suppression of luteinizing hormone (change 1.3 units/L; p=0.003) levels.

The latter, i.e. the reduced luteinizing hormone levels are what actually suggests that we are dealing with a direct effect at the testicular level and not some weird hyptohalamic feedback. A centrally mediated in crease in testosterone production would after all have gone hand in hand with in- not decreases in luteinizing hormone concentration.

Minimal changes in adrenal hormones

With small, but noticeable increases in androstenedione and oestrone increased by 1.3 nmol/L (38 ng/dL; p=0.011) and 10.7 pmol/L (2.9 pg/mL; p=0.012), Spitzer et al. cannot exclude that the sildenafil induced phosphodiesterase-5 inhibition did also affect the adrenal glands - or, to be precise, "late adrenal androgen synthesis" (Spitzer. 2013):

Gingko = Brain Viagra?

"The adrenal glands are the major site for production of androstenedione, which is converted to oestrone by aromatase. Enzyme 17,20 lyase, which converts 17a-hydroxyprogesterone to androstenedione, is upregulated with sildenafil treatment in rats.

This could explain the increase in serum androstenedione levels in our participants. However, an increase in 17,20-lyase activity should also result in an increase in DHEAS levels, which was not observed. Further investigation is needed to study the effect of sildenafil on adrenal androgens." (Spitzer. 2013)

While the exact mechanism that's responsible for the androstenedione increases must still be determined, it is, as previously mentioned, almost certain that the increase in testosterone levels was mediated by direct effects on the steroidigenic leydig cells in the testes. They are the ones that respond to the luteinizing hormone signalling from the brain have been reported to respond directly to PDE-5 inhibitors in previous studies by Andric et al. from 2007 & 2010, as well as Janjic et al. from 2012.

More sex = more testosterone?

Whether and to which extend the increase in testosterone has also been indirectly promoted by increases in sexual activity, which have been previously reported to lead to increases in testsosterone levels after successful treatment of erectile dysfunction (Aversa. 2013) remains to be seen. The data from the study at hand does at least not support this notion, because a "greater sexual activity did not predict greater change in serum total testosterone" (Spitzer. 2013).

Other studies have associated greater sexual arousal with acute increases in LH and subsequent increases in testosterone production (LaFerla. 1978; Rowland.1987). With decreasing not increasing LH levels being one of the main findings of the study at hand, it is however more or less impossible that the increased sexual desire was the horse, not the cart in the sildenafil-related increases in testosterone levels Spitzer et al. observed in their 140 borderline to full-blown hypogonadal man.

SuppVersity Suggested Read: "Will Sex Before a Competition Hamper Your Performance? Plus: How Can Estrogen, Cortisol, Quail and Muhammad Ali Help Us Answer This Important Question" | read more

Bottom line: It appears to be settled that it is the direct effect of PDE-5 inhibition on testicular testosterone production that's responsible for the Viagra induced increases in testosterone production. What is not settled, though and I guess that is something people tend to forget about, when they hear promising study results like  these is that the benefits were observed in a men whose testosterone production was already impaired.

In fact, the researchers' acknowledgment that "some portion of the observed increases in testosterone occurring during sildenafil administration is almost certainly attributable to regression to the mean" (Spitzer. 2013) would suggest that similarly pronounced effects cannot necessarily be expected in men with normal testosterone levels... but hey, the same goes for 99.9% of the OTC "test boosters" and people still buy them despite the fact that they do not even have produce those "nasty" boners as a side effect ;o)

References:

• Andric SA, Janjic MM, Stojkov NJ, Kostic TS. Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E544-50.
• Aversa A, Jannini EA, Maggi M, Lenzi A. Effects of testosterone replacement on response to sildenafil citrate. Ann Intern Med. 2013 Apr 2;158(7):569-70.
• Janjic MM, Stojkov NJ, Bjelic MM, Mihajlovic AI, Andric SA, Kostic TS. Transient rise of serum testosterone level after single sildenafil treatment of adult male rats. J Sex Med. 2012 Oct;9(10):2534-43.
• LaFerla JJ, Anderson DL, Schalch DS. Psychoendocrine response to sexual arousal in human males. Psychosom Med. 1978 Mar;40(2):166-72.
• Rowland DL, Heiman JR, Gladue BA, Hatch JP, Doering CH, Weiler SJ. Endocrine, psychological and genital response to sexual arousal in men. Psychoneuroendocrinology. 1987;12(2):149-58.
• Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013 Nov;1(6):913-8.

Science Round-Up Seconds: Does the Paleo Diet Ruin Your Lipid Profile? Plus: Liver Health & Hepatitis - Milk Thistle & Beyond. Libido Boosters & Real PDE-5 Inhibitors. "Fake" Cinnamon, Coumarin, Bloodthinning & Carcinogenic Cereals.

Is the Paleo Diet unhealthy for healthy individuals? A recent thesis would suggest just that. Learn more about and make up your mind based on the last installment of the Science Round-Up and today's Seconds (img informedhealth.com.au)

I hope you did not miss that the SuppVersity Science Round-Up will as of now always be starting early(-ier) at 12PM EST. If so, don't worry, you can still download the show and listen to Carl and me talking about the things you may be missing, the ones you get extra and those you would rather not have in your supplements and foods. Let's take silymarin, for example, as you have learned on the show, not all "liver assist", "liver clense" or "liver health" products are created equal. Most intriguingly, their ability to scavenge free radicals, as measured by the trolox assay, is not singularly dependent on the actual silymarin content, but will - as the data from the study Anthony et al. conducted (Anthony. 2013) - vary largely, depending on where the milk thistle was grown, how it was processed and thus what else, aside from the purportedly active ingredient is in it.

There is more to natural products than a single active ingredient

If you will, the "there is more to it" was a golden thread that ran through the whole show, but before we follow it up to the next topic, I want to provide you at least an excerpt from the actual data Anthony et al. produced.

Table 1: Selected products tested in the study ordered by their anti-oxidant activity in the TROLOX essay; products with highest TROLOX and anti hepatitis C viral activity highlighted in green and violet, respectively (Anthony. 2013)

As you can see my selection of the 45 products, the scientists bought and tested, reflects what you have already heard on the show: The silymarin content varies largely. In essence, the actual silymarin content may yet not even be that important. If you focus solely on their TROLOX equivalents (TROLOX is a vitamin E like antioxidant and it is used to quantify the anti-oxidant activity in a standardized way - more or less like the meter is used to quantify the length of an object or seconds are used as a standard timespans are expressed in).

More about Liv-52: Actually, the Himalaya(R) product is one of the few OTC supplements with not just one, but more than 20 studies to back its hepatoproctective and antioxidant effects. One thing to keep in min about the research is though that it was - despite being mostly published in peer-reviewed journal - in large parts conducted by scientists who work either for or with the company. As I've pointed out previously, this does not mean that the data is flawed, but it puts observations such as the improved glucose uptake (213%) , the 50% reduction in triglyceride content (anti-NAFLD effect), the 790% increase in glutathione, as well as the decreased TNF-α (-51%) and IL-8 (-550%) and concomitant -65% and -69% reductions of lipid oxidation and DNA fragmentation, respectively, Vidyashankar et al. observed in a recent in-vitro study somewhat into perspective (Vidyashankar. 2012).

If you are looking for the most potent among the readily available products in my selection the most potent "liver protectant" would actually be the PED user's first choice Liv-52, which does not even contain silymarin but is based on an undisclosed amount of  capers (Capparis spinosa), wild chicory (Cichorium intybus), arjuna (Terminalia arjuna), negro coffee (Cassia occidentalis), yarrow (Achillea millefolium) and tamarisk (Tamarixgallica). Bio Silymarin by Advanced Beta Glucon Therapy, on the other hand, is a close second with an almost identical TROLOX value (9.4 vs. 9.5 for Liv-52), is based on silymarin; plus, it exerts 77% more pronounced hepatitis C virus (HCV) antiviral activity than the Himalaya product which lists "viral hepatitis" as the #1 indication on the corresponding website.

As far as these anti-HCV effects, which were standardized against the results the scientists observed in cultures that were treated with 100 U/mL interferon-α, are concerned another Source Natural's Silymarin Plus, emerged as the most potent product. With the "plus" signaling the addition of choline, inositol, vitamin C+E, this observation confirms that antioxidant activity and anti-viral activity are two pairs of shoes - even when the active ingredient (silymarin) is the same.

Apropos active ingredient

You are yet by no means at the mercy of milk thistle and silymarin, when you want to protect your liver from harm. Spices like

• Tumeric (curcumin)
• Coriander

• Garlic
• Red chili
• Black pepper

bust also coffee and green tea, and fruits and vegetables such as

• carrots
• ivy guard
• sweet corn
• soy (for the glycine in it)

• grapes
• custard apples
• Indian gooseberries
• pomegrenade
• sea buckthorn

have potent anti-oxidant and antiproliferative activities (Shukla. 2013)

OTC libido boosters - more than just an alternative

Now that we are talking about alternatives, let's get straight to the next one: The "alternative" to viagra, cialis & co. Honestly, I would hope that you will never have to use one of these (I suggest you take a peak at yesterday's post "The '20 / 30 Principle' Sheds 15% Body Fat in 6 Months, Boosts Testosterone & Sexual Performance in Overweight Men. Plus: Six Signs You're Doing Too Much, Already."; read more), but in the unfortunate case you do, you may be surprised how effective the majority of them actually is.

Figure 1: Categorial breakdown of the adulterated majority of the 91 products from the Campbell study (Campbell. 2013)

A brief glance at the data in figure 2 does yet suffice to see that this is not another case of the "nature knows best principle", but simply a consequence of the fact that the majority of these products do contain either sildenafil and/or taldalfil or some sort of molecular cousin ("analogs" in figure 2). Moreover, in 18 out of these products the dosage was >110% of what would be legit on a per serving base for the prescription varieties (I suspect this is 20mg).

Also mentioned in this context: Saw palmetto is a PDE-5 inhibitor (cf. Yang. 2013). Although the evidence is from a rabbit study, it's pretty likely that there will be at least some discernible effects of saw palmetto on PDE-5 activity an iNOS activity in the human corpus cavernosum, as well.

Coumarin: Carcinogenic & blood thinning cereals

Table 2: Coumarin content in mg/100g of the samples from the Wang study

As unfortunate as it may seem, the chance that the cinnamon you consume with pre-packaged food is "real" (=verum) and from the inner bark of Cinnamomum verum are close to zero. Since this is however the only variety, where you can be almost 100% sure that you don't consume blood thinning and pro-carcinogenic coumarin, it does actually not come as a surprise that cinnamon apple sauce or a cinammon roll bought from the local supermarket contain 0.64 and 2.1mg of this agent on a per serving basis.

If you take a closer look at the rest of the data Wang et al. collected for their latest study (Table 2; cf. Wang. 2013), you may be surprised to see that regular bread, generally unsuspicious oats and purportedly healthy granola bars contain coumarin in amounts that will have you easily surpass the daily uptake limit of 0.1 mg/kg body weight, which was established by the European Food Safety Authority (EFSA) right after it became clear that coumarin is a potential carcinogen... *yamyoll*

Nedless to say that the consumption of respective supplements, which are currently heavily marketed as healthy anti-diabesity agents, could do more harm then good, when the producers play it cheap and put the next best "Cinnamomum XY" they can get their hands on into the caps.

Neither viagra nor cinnamon caps are "paleo", yet still...

E. Trexler titled his recently published thesis "Paleolithic Diet is Associated With Unfavorable Changes to Blood Lipids in Healthy Subjects", which would suggest that the paleo diet is similarly unhealthy as the consumption of "fake", coumarin-loaden cinnamon or high amounts of isolated cholorogenic acid (story is discussed in detail in the podcast; cf. Mubarak. 2013).

Figure 2: Lipid profile (left; values expressed in % of reference levels), fitness and body fat level (right) before and after the Paleo + Crossfit interention (calculated based on Traxel. 2013)

If you take a closer look at the abstract and the actual "side effects" (figure 2), the 10-weeks of paleo dieting + CrossFit-based, high-intensity circuit training exercise program had on the body composition and fitness levels, I personally cannot but ask the following question:

 "What is the significance of the elevations in LDL and minor reductions in HDL in a scenario that produces exactly what has just been shown to be at the heart of the 'Obesity Paradox' and lipid values that are still within the ever-narrowing 'normal' or 'optimal' range?"

I'll leave it up to you to answer this question and decide whether it can really be so bad to rid yourself of all modern, processed foods including any form of processed sugar, soft drinks, and coffees, while fueling your life and workout related energy by increasing your consumption of lean meat, fish, eggs, nuts, fruit, and vegetables. Have a nice weekend!

References:

• Anthony K, Subramanya G, Uprichard S, Hammouda F, Saleh M. Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements. Antioxidants. 2013; 2(1):23-36.
• Campbell N, Clark JP, Stecher VJ, Thomas JW, Callanan AC, Donnelly BF, Goldstein I, Kaminetsky JC. Adulteration of Purported Herbal and Natural Sexual Performance Enhancement Dietary Supplements with Synthetic Phosphodiesterase Type 5 Inhibitors. J Sex Med. 2013 May 1. 
• Mubarak A, Hodgson JM, Considine MJ, Croft KD, Matthews VB. Supplementation of a high-fat diet with chlorogenic Acid is associated with insulin resistance and hepatic lipid accumulation in mice. J Agric Food Chem. 2013 May 8;61(18):4371-8. 
• Shukla SK, Kumar V. Bioactive Foods and Supplements for Protection against Liver Disease. In: Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease. Elsevier. 2013. 
• Trexler, E. Paleolithic Diet is Associated With Unfavorable Changes to Blood Lipids in Healthy Subjects Honors Research Thesis. Ohio State Univeristy. May 2013.
• Vidyashankar S, Sharath Kumar LM, Barooah V, Sandeep Varma R, Nandakumar KS, Patki PS. Liv.52 up-regulates cellular antioxidants and increase glucose uptake to circumvent oleic acid induced hepatic steatosis in HepG2 cells. Phytomedicine. 2012 Oct 15;19(13):1156-65.
• Yang S, Chen C, Li Y, Ren Z, Zhang Y, Wu G, Wang H, Hu Z, Yao M. Saw Palmetto Extract Enhances Erectile Responses by Inhibition of Phosphodiesterase 5 Activity and Increase in Inducible Nitric Oxide Synthase Messenger Ribonucleic Acid Expression in Rat and Rabbit Corpus Cavernosum. Urology. 2013 Apr 23. doi:pii: S0090-4295(13)00169-6.

The "20 / 30 Principle" Sheds 15% Body Fat in 6 Months, Boosts Testosterone & Sexual Performance in Overweight Men. Plus: Six Signs You're Doing Too Much, Already.

One out of four men with newly diagnosed erectile dysfunction is under 40 (more)

You will probably remember the post about the increasing prevalence of erectile dysfunction in young(er) men on Facebook, the other day (learn more)!? As of now, one out of four patients who are newly diagnosed with erectile dysfunction are 40 years or younger. That's an alarming trend that certainly cannot be reversed by the use of adulterated OTC libido boosters with high amounts of pharmacological PDE-5 inhibitors that are not listed on the label (read more on the SuppVersity Facebook Wall and listen live to today's installment of the Science Round Up starting at 12PM EST!). With  30-40% of the overweight men not being able to achieve an erection of maintain it long enough to engage in sexual intercourse, it stands out of question that the root cause for the exploding numbers of impotent young men is diabesity.

Against that background it is only logical that Joan Khoo and his colleagues from the Department of Endocrinology at the Changi General Hospital, the Departments of Sports Medicine and Rehabilitative Services at the Changi General Hospital assumed that diet and exercise should be more than an alternative to drug interventions. The latter has in fact been established in numerous previous studies, already. In obese Australian men who lost an average of 10% of baseline weight from caloric restriction alone using meal replacements or a low-fat diet and in men after 2 years of weight loss using Mediterranean diet and exercise, for example, the test scores in the International Index of Erectile Function 5-item (IIEF-5) improved by ~20% (Khoo 2011; Esposito. 2004).

Exercise works, but how much exercise does it take?

What has been missing up to know is yet a study that would establish the amount of exercise that's necessary to boost the existing benefits of energy restriction. And guess what!? That's exactly what Khoo et al. set out to do - conduct a trial that would compare the effects of 24 weeks of ...

• low volume medium intensity exercise training (<150 minutes/week) and
• (relatively) high volume medium intensity exercise (>200m/w) training

on the body weight, waist circumference (WC), body composition, International Index of Erectile
Function 5-item (IIEF-5), International Prostate Symptom Scale (IPSS) (for LUTS), and 36-item Short Form Survey version 2 Instrument (SF-36) (for QoL) scores, plasma testosterone, sex-hormone binding globulin, glucose, insulin and lipids, and endothelial function (by Reactive Hyperaemia Index [RHI] using finger plethysmography) of 90 abdominally obese Asian men (BMI >27.5 kg/m²; WC>90 cm; mean age 43.6y), who ha not moved an inch all day long in the past years (average amount of "exercise" ~80 minutes/week).

Freedom of choice: Exercise when and where you want

The aerobic only *sigh* exercise program could be performed on whatever equipment / sportive activity the subject like - stationary cycling, treadmill, elliptical crosstraining, brisk walking, jogging, cycling, and swimming, all were eligible for 90–150 minutes/week - the subjects were free to chose and pick, but they had to record type and exercise duration and make sure that they would hit their target heart rates of 55–70% of their individual maximal heart rate (HR_max=220-age) on whatever they did.

Figure 1: Absolute (body composition) and relative changes (lipids, sex hormones & erectile function); after 6 months on the diet + low vs. high volume exercise regiment;LUTS = lower urinary tract symptoms; IIEF-5 = International Index of Erectile Function 5-item questionnaire; IPSS = International Prostate Symptom Scale; SF-36 PCS and MCS = 36-item Short Form Survey version 2 Instrument Physical Component Summary and Mental Component Summary scores (Khoo. 2013)

In combination with the obligatory reduction in energy intake (-400kcal/day; ~15-20% of their baseline intake) both groups made significant progress. In comparison to the -4.7kg of body fat the guys in the "high volume" group (I use the quationmarks to emphasize that I would not consider ~30min of exercise/day exorbitantly high, considering the fact that the this was cycling, walking or swimming at a relatively moderate intensity) lost in the course of the 6-months intervention, the -1.1kg of total fat mass the guys in the low volume group dropped do yet look pretty pathetic.


"Doing more" for total & free testostosterone!?

What are signs that you are already doing too much ?

• constant fatigue that does not disappear, when you take a day off and get enough sleep (too much volume)
• inability to fall asleep (too much high intensity work)
• inability to sleep through (too much volume)
• getting up to pee every 1-2h (too much volume, too few carbs vs. too much protein)
• the 4am wake-up call = inability to sleep through (see above, fasting in the evening)
• no fat loss despite caloric deficit (eating too little + high training volume)
• losing muscle, not fat (too much volume, too much medium intensity cardio)
• low sex hormones / drive, low thyroid function, high rT3 (too much volume, too much protein, too little fat & carbs, not eating enough)

If you want more insights, you can find them in the Athletes Triad Series.

If we take a look at a couple of other parameters the scientists evaluated, you will notice a clear dose-response relationship. Much contrary to the participants in the Rosenklide study, I wrote about in 2012, which had a much higher training volume and intensity, doing more did - within this narrow relatively low volume moderate intensity regimen - did thus really yield superior results. Even more, the dose-response relationship is almost linear: 2x more exercise, 2x more weight loss, 2x more fat loss, 2x greater reduction in insulin, 2x greater reduction in blood glucose.

For testosterone (>2x more) and free testosterone (almost 5x more), the benefits were even more pronounced and the difference between the ratio of fat and lean mass lost 6.7 for the high vs. 5.5 for the low volume group are certainly not to be scoffed at, either.

Still, we just have to go back to the counterproductive effects Rosenkilde et al. observed in their study (go back and learn more), to see that the 30 minutes of exercise per day are probably not the end of the flagpole, but a very happy medium beyond which previously untrained individuals, and experienced trainees who work out at a correspondingly higher intensity level, could hit a wall and spiral down into the abyss of chronic overtraining - especially when exercise habits like that are combined with a diet that does not only induce an energy deficit of 20% but does at the same time make it particularly hard for the body to use the energy it gets... yep, I am talking about the notorious high protein, low carb, low fat diets the scaremongerism on both sides of the low-carb vs. low-fat divide have made so popular (learn more).

---

Bottom line: Diabesity, erectile dysfunction and hypogonadism? The solution to this triad is there! It's not complicated, but it requires commitment, it requires discipline and it will cut your daily screen time by 30 min... if you or your overweight friends don't feel that this is worth it, let them waste their money and risk their health by jumping from one "quick fix" solution and diet (e-)book to the other. If not, write the numbers "20/30 x 6" on a DinA4 sheet and pin that to your or your friends' fridge to remind yourself or them that it takes a caloric reduction of 20% + 30min of moderate intensity exercise and the stubbornness to adhere to that protocol for 6 months day in day out (I guess 90% compliance would even be enough) to take a huge step on your way towards normalizing your body composition, glucose and lipid metabolism and endocrine and erectile function... and on a last note: I bet this works for overweight women with PCOs, as well.

References:

• Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D’Andrea F, D’Armiento M, Giugliano D. Effect of lifestyle changes on erectile dysfunction in obese men: A randomized controlled trial. JAMA 2004;291:2978–84.
• Khoo J, Piantadosi C, Duncan R, Worthley SG, Jenkins A, Noakes M, Worthley MI, Lange K, Wittert GA. Comparing effects of a low-energy diet and a high-protein low-fat diet on sexual and endothelial function, urinary tract symptoms, and inflammation in obese diabetic men. J Sex Med 2011;8:2868– 75.

Natural Sildenafil & Testosterone Alternatives: Pedalium Murex & Paederia Foetida +150% Testosterone and +200% Erectile Function. Plus: Icariin, Aromatase & Stronger Bones. Probiotics, Phytosterols & Thyroid Activity.

If the Aliens have seen these Bugarash apocalypse pilgrims, they have probably turned tail and fled ;-)

I guess the SuppVersity figure of the week was a date "12/21/2012", I mean this is a once in a life-time event! Or do you really believe there will be another chance for mankind to be snatched from the jaws of extinction?

Ok, enough of the sarcasm, the world is still there and the SuppVersity is still operating, so let's get to the not so short On Short Notice items for today.

If there had been more room in the headline I would probably have labeled it "Endocrine Special" and I guess once you have gone through the posts, you will agree that this would certainly have made sense.

• Traditional treatment of osteopenia with Epimedium brevicornum works, 'cause it's a potent aromatase promoter (Yang. 2012) -- When a group of researchers from the Chengdu Institute of Biology, Chinese Academy of Sciences and the School of Chinese Pharmacy, Chengdu University of Traditional Chinese Medicine in Chengdu, China, set out to investigate the mechanism behind the anti-osteoporotic effects of the dried leave extract from Epimedium brevicornum, they already suspected that it would probably be related to some sort of endocrine modulation.
  
  

  

  Figure 1: In vitro effect of Forskolin and Icariin on aromatase expression in KGN cells (Yang. 2012)

  With estrogen deficiency being the major cause of osteoporosis, a disease which does by the way affect over 200 million people worldwide (Riggs. 1998), being their the most likely mechanism behind the bone building and bone mineral density (BMD) protective effects, it was obvious to study, whether there was some sort of interaction between the extract and the data in figure 1 shows that Yang et al. were right to do so (note: the cell line used in the study was a KGN granulosa cell that's closely associated with the developing female oocyte, so effects could vary from one tissue to the other)
  
  Now all that certainly sounds as if this was bad stuff no sane male human being should be taking. Luckily, for many of you, my fellow men, who may have been exposed to Epimidium / Icariin from various supplements, this is not the case. Why? Simply because estrogen is not the enemy and Epimidium has not only been found to have anti-aging effects (whole extracts; Yan. 2009), it also prevents neurotoxicity from beta-amyloid plague the key feature of Alzheimer's and similar diseases (Zeng. 2010; listen to Thursday's Science Round-Up for other amyloid beta inhibitors / protectant's) and the neurotoxic effects of excess corticosteroids (Liu. 2011). In addition, Epimidium pubescen flavenoids have been shown to reverse the negative effects even passive exposure to cigarette smoke may have on the bone mineral density of male rats (Gao. 2012) and Icariin the common denominator in all of the members of the Epimidium family exerts direct proliferative and thus pro-fertility effects on the sertoli cells in male rodents (Nan. 2012).
  
  

  

  Table 1: Analysis of Chinese Epimidium species (MDida. 2010)

  Ah, and last but not least the beneficial effect Horny Goat Weed (likewise one of the members of the Epimidium family) has on male libido are likely partly a result of the increased aromatase activity, as well. If it works for you, your estrogen levels are probably pretty low to begin with (this reasoning is based on the profound beneficial effects of estrogen on male libido in men expressing little to no aromatase enzyme; Carani. 1999).

• Pedalium murex Linn. fruits may not be as potent acute libido and erectile performance enhancers as sildenafil, but the effects accumulate and persist just as its unique testosterone boosting effects (Sharma. 2012) -- In case taking a potential proestrogenic compound like Horny Goat is nothing you feel would do anything good for your libido, you may want to use some Pedalium murex Linn. in traditional Indian medicinea herb that has been used in traditional Indian medicine for centuries to treat male sexual dysfunction and impotency.
  

  

  Figure 2: Effects of different doses of an ethanolic extract from Pedalium murex (P.m.) and Sildenafil citrate (5mgkg) on penile erection scores and post ejaculatory interval (time it takes to be able to have sex again) exrpessed relative to saline treated control (based on Sharma. 2012)

  As the data in figure 2 shows, its effects on erectile performance are slightly less pronounced than those of sildenafil citrate, but at an appropriate dosage and after some time, it will probably do its job sufficiently for most men with respective problems. What's really exiting though, is that the data in figure 3 clearly shows that it does so not by simple nitric oxide effects (P. murex at 10 mg/
  ml exhibited a relative nitric oxide release of 15.3 mM as compared to a nitric oxide release of 39.3472.7 mM with sildenafil citrate), but probably (also) by boosting testosterone levels. 
  
  

  

  Figure 3: Serum testosterone levels during and after Pedalium murex or Sildenafil citrate administration expressed relative to saline control (Sharma. 2012)

  Since the testosterone levels remained elevated for 14 days after the treatment was seized these observations make P. murex a potential candidate for the next best natty test booster.to be powered by advertisement lines like "up to 125% increase in testosterone that last for more than 2 weeks" even when you take some time off. I guess, the only serious downside here is the close relation of P. murex to the notoriously useless Tribulus, which does also contain furostanol glycosides. Luckily Magnle and Jolley found another potentially active ingredient in P. murex fruit. The compound goes by the name diosgenin and appears to be a direct precursor for the synthesis of sex hormones including testosterone (Mangle. 1998).
  
  Since I don't think you will have to wait very long until the first major players in the supplement business will jump on this bandwagon - you know that a single rodent study is enough to make fortune until people realize that this stuff does not work, at all - you will probably soon be able to test it on yourself. In case you intend to do that, you should certainly look for a standardized ethanolic extract with ~20%+ of diosgenin (that was the content of the extract Sharma et al. used) and a serving size of 16.2mg/kg per body weight, the HED of the 100mg/kg group (that would be 1,300mg /day of the extract for an 80kg adult).

• Paederia foetida Linn. (P. foetida) yet another Indian libido and testosterone boosting herb (Soni. 2012) -- If you like the appeal of exclusiveness a climbing plant found in the Central and Eastern Himalayas, at elevations of up to 5000 ft, you may prefer the an ethanol extract of Paederia foetida Linn. (P. foetida) leaves over the previously discussed Pedalium murex fruit extract.
  
  

  

  Figure 4: Penile erection index and testosterone levels of rats after 15 and 28 days on P. foetida, data expressed relative to saline control (Soni. 2012)

  According to a recent study from the same group of Indian scientists (yet a different lead author), the effects of P. foetida and P. murex are in fact virtually identical. While the general protocol was very similar (in this done on rat, not mice) the positive control was not Sildenafil citrate, as in the previously mentioned experiment, but an intramuscular injection of 0.5 mg/kg body weight of testosterone suspension in arachis oil twice a week. It's actually a pity the scientists didn't measure the actual testosterone levels in the animals in the testosterone group. I would be curious how the 2.5x increase in the high dose group (200mg/kg, human equivalent ~2,600mg/day) would compare. When it comes to the erection quality, it did at least easily top the results of injectable testosterone (see figure 4), which is yet allegedly not the best erection booster, anyway. And if we went by the data on body weight and the weight of the testes, seminal vesicles, prostate glands and epididymis, it even appears to be more anabolic than testosterone; after all the body weight gain in the PF groups were 15%. 23% and 34% higher than in the control group and comparable if not higher to those that were induced by testosterone (+29%).
  
  And for all the supplement producers and fans of stacks it may be important to know that the leaves of P. foetida, which is also used as carminative, antiinflammatory, astringent, spasmolytic, antidiarrhoeal, diuretic and antilithic do contain a whole host of well- and lesser known compounds, e.g. iridoid glycosides, sitosterol, stigmasterol, campesterol, ursolic acid, hentriacontane, hentriacontanol, ceryl alcohol, palmitic acid and methyl mercaptan, but no diosgenin. So Ayurvedabol (TM) or whatever name ending on -bol, -drol or -ripp-off has not been used by the creepy competition, already, could benefit from having both Paederia foetida and Pedalium murex in it ;-)

• Combination of probiotics and phytosterols ramps up thyroid function and (re-)establishes a healthy lipid profile (Awaisheh. 2012) -- While I could offer you a minimum of two additional libido enhancing, potentially pro-anabolic testosterone booster, I know that not all of you are into these products (am I right ladies?), so I thought it prudent to close this installment of On Short Notice with a study on thyroid metabolism, which could be is of interested for all of you.
  
  
  Which phytosterols are there and where can I find them? The major phytosterols in the human diet are sitosterol (high in nuts, amaranth, avocados, grape leaves), stigmasterol (high in coriander, chocolate and soy), campesterol (high in various vegetable oils, spec. conola / rapeseed) and brassicasterol (high in cabbage, broccoli, other brassica, but also coriander, seafood and rapeseed oil).
  Contrary to some previous studies and anecdotal reports on the Internet, a recent paper by scientists from the Department of Food Science at the Al-Balqa Applied University, in Salt, Jordan, suggest that phytosterols don't have thyroid inhibiting, but promoting effects.
  
  In their latest study Awaisheh et al. investigated the effects of a probiotic stack containing two strains of each of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus reuteri and a phytosterol supplement on the lipid metabolism in rodents. Their results show that the addition of the phytosterol supplement promoted the already pronounced effects the probiotics had on the hypercholesterolemia of the rodents who were fed with a high-fat-high-cholesterol basal diet for 8 weeks. In addition, the phytosterols, yet not the probiotics alone, elevated the levels of serum total thyroxine (TT4), total triiodothyronine (TT3), and free triiodothyronin (fT3), which could have exerted additional benefits on the non-measured triglyceride levels.
  
  These results do actually come as a surprise and I would like to see more research - specifically in human trials - before I would buy products from producers who seize the scientists suggestion that this renders probiotics and phytosterols potential candidates for "functional foods" - I mean, let's be honest ever since the first "functional foods" hit the market people have been getting sicker: Do you really believe that's because they don't eat the "good" cholesterol lowering margarine instead of their beloved Kerrygold butter? I don't think so.

That's it for today.. well, aside from the promise to include the other testosterone and libido boosting herb studies in another SuppVersity post and a selection of the latest  SuppVersity Facebook News, of course:

• Iron deficiency makes H Pylori go on a rampage - Iron deficiency enhances H. pylori virulence and increases risk of gastric cancer (read more)
• Danish folk medicine for depression? Not really, but there are a couple of promising natural MAO-A inhibitors the Danes have been using for centuries (read more)
• Strength training equally heart healthy as aerobics - 6-weeks of strength training show particular beneficial effects in African American men (read more)

Since I it's still pretty early and I am certainly not going to the city, before the shops close and all the people who believed they wouldn't need Christmas presents this year, since the world would *put whatever apocalyptic catastrophe you like here*, have gone home, I may be adding some more news later. Until then, I hope you have some fun with what's already there and are looking forward for the 2nd installment of the "Making HIIT a Hit" series that will be published tomorrow.

References:

• Awaisheh SS, Khalifeh MS, Al-Ruwaili MA, Khalil OM, Al-Ameri OH, Al-Groom R. Effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats. J Dairy Sci. 2012 Nov 22.
• Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata AR. Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency. Clin Endocrinol (Oxf). 1999 Oct;51(4):517-24.
• Gao SG, Liu H, Li KH, Liu WH, Xu M, Jiang W, Wei LC, Zhang FJ, Tian J, Xiao WF, Yang Y, Song Y, Lei GH. Effect of Epimedium pubescen flavonoid on bone mineral density and biomechanical properties of femoral distal end and femoral diaphysis of passively smoking male rats. J Orthop Sci. 2012 May;17(3):281-8.
• Liu B, Zhang H, Xu C, Yang G, Tao J, Huang J, Wu J, Duan X, Cao Y, Dong J. Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. Brain Res. 2011 Feb 23;1375:59-67. 
• Mangle MS, Jolley CI. HPTLC studies on Tribulus terrestris (Chota ghokru) and Pedalium murex (Bada ghokru). Indian Drugs. 1998; 35:189–194.
• MDidea Extracts Professional. Horny Goat Weed or Epimedium Herb: Botanical Origin, Archeology, Traditional and Pharmacological findings of Epimedium species, fractions and isolated components. 08th, Oct. 2010. < http://www.mdidea.net/products/herbextract/icariin/data10.html > retrieved on 12/21/2012. 
• Nan Y, Zhang X, Yang G, Xie J, Lu Z, Wang W, Ni X, Cao X, Ma J, Wang Z. Icariin stimulates the proliferation of rat Sertoli cells in an ERK1/2-dependent manner in vitro. Andrologia. 2012 Nov 7.
• Riggs BL, Khosla S, Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998 May;13(5):763-73. 
• Sharma V, Thakur M, Dixit VK. A comparative study of ethanolic extracts of Pedalium murex Linn. fruits and sildenafil citrate on sexual behaviors and serum testosterone level in male rats during and after treatment. J Ethnopharmacol. 2012 Aug 30;143(1):201-6.
• Soni DK, Sharma V, Chauhan NS, Dixit VK. Effect of ethanolic extract of Paederia foetida Linn. leaves on sexual behavior and spermatogenesis in male rats
• Yan S, Wu B, Lin Z, Jin H, Huang J, Yang Y, Zhang X, Shen Z, Zhang W. Metabonomic characterization of aging and investigation on the anti-aging effects of total flavones of Epimedium. Mol Biosyst. 2009 Oct;5(10):1204-13.
• Zeng KW, Ko H, Yang HO, Wang XM. Icariin attenuates β-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells. Neuropharmacology. 2010 Nov;59(6):542-50.

Human Study: OTC Supplement Doubles T-Levels & Boosts Erections More Than Tadalafil - Too Good to Be True?

Just to make sure you don't suffer from withdrawl symptoms until Adelfo posts the next update on his current contest prep, I thought I'd share a photo that shows where he is currently at - not bad for someone of whom a handful of you have been shocked to hear that he eats at least 200g carbs per day and ice-cream almost every evening, right?

It's Thursday and before I'll get to a question on a very recent study I received via the SuppVersity Facebook page, I will brief you on the line-up of today's installment of the SuppVersity Science Round-Up on the Super Human Radio Network. By now, most of you should actually be familiar with the modus operandi: In case you cannot listen live at 1PM EST, you can always download the show ~2h later either from the "Physical Culture for Your Ears" menu in the sidebar of the SuppVersity, or right over at www.superhumanradio.com - obviously, you can also wait for tomorrow's SuppVersity Science Round-Up Seconds, in which I am providing some additional information on things we have discussed and post selected topics that did not make it into the show.

Apropos topics, the first topic we are going to address does actually pertain to the second part of this post and revolves around a recently published paper by Fabrizio Iacono et al. whose results do - just as SuppVersity reader Mark, who pointed me towards this article, says - look "too good to be true".

Now, upon closer scrutiny it turns out that they may well be "true", but are not just as "good" as they may initially look like. From this testosterone-laden topic we are then going to proceed with topics revolving around male and female longevity, optimal workout types and intensities for different trainees, the health effects of garlic, colostrum and chocolate and related topics.

I could mention more, but am afraid that this will just increase the risk of rushing through the items too quickly. Optimally, you just tune in live and pick up the rest in "print" in tomorrow's SuppVersity Science Round-Up Seconds!

200% increase in total and 130% increase in free testosterone

Just a reminder: Taurine has also (rodent) data showing up to 180% increases in testosterone and that's not exclusively in the sick and old.

This subheading sounds as if I was to pimp the "revolutionary new testbooster" by "whatever company" that will get you muscular and ripped in no time, right? Well, in the end it could well be the text of an advertisement, yet not one from any of the usual suspects but rather one for TRADAMIX®, a blend of "three natural substances with an 'anti-aging' effect on the tissues of the male genitourinary apparatus" (Tradapharma Sagl. 2012) - I know, without the usual "-bols", "-diols", or at least some indirect references to illegal anaobolic substances in the product name, this does not sound like it would work, but the +200% increas in total and +130% increase in free testosterone are for real and documented in a peer-reviewed study involving seventy patients (67.3± 3.7 years) with stable marital relations and reduced libido, with or
without erectile dysfunction who received either the infamous PDE-5 inhibitor Tadalafil (5mg/day) or two servings of the aforementioned 'testicular anti-aging supplement' (Iacono. 2012).

But before we even get to the testosterone levels, let's tackle the main problem of these guys and the actual research interest of the scientists from the University “Federico II” of Naples in Italy first. After all, the main outcome of the study at hand were the improvements in sexual desire and erectile function and those were almost identical in both groups - from 16 to 33 and 16 to 31, in the supplement vs. drug groups, respectively. If you go by the results of the international index of erectile function (IIEF) questionnaire (see figure 1, left), on the other hand, the dietary supplement yielded actually outperformed the blockbuster prescription drug by almost 10%:

Figure 1: Results of international index of erectile function (IIEF) questionnaire and RigiScan (device to measure penile tumescence and rigidity continuously that's used to differentiate vascular from psychogenic erectile dysfunction) before and after 2 months of treatment with Tradamixina and Tadalafil (Iacono. 2012).

What's probably even more impressive, though, are the differential effects of Tradamixina vs. Tadalafil on the RigiScale values (see figure 1, right). The RigiScale is an etablished means to differentiate psychogenic from organ-related (vascular) erectile dysfunction (Basar. 2001) and the fact that there was a significant reduction of RigiScale positive subjects in the Tradamixina group does already suggest a possible reason for the initially mentioned 200% increase in total and 130% increase in free testosterone (see figure 2).

Figure 2: Total and free testosterone levels before and after the administration of Tradamaxine (2 servings per day) or Tadalafil (2mg/day) to Seventy patients (67.3± 3.7 years) with stable marital relations and affected by reduced libido for 2 months (data based on Iacono. 2012)

What this underlying reason is? Well, probably reduced systemic inflammation, which leads to reductions in cortisol, blood glucose, insulin resistance, oxidative damage to the testes etc. and thus simply facilitates the restoration of normal testosterone levels.

If you know how google works, it'll take you maybe 5 minutes and a credit card and you'll have a couple of pounds of the ingredients right on the way to your doorstep.
Yep, you heard me right: A boost of +200% just brought those guys who started with 10ng/dl below the already way too broad normal range from 260-1080ng/dl (values may vary from lab to lab) in a quasi hypogonadal state, back to midrange levels of 680ng/dl.

Real world implications for healthy young men: The chance that a healthy, fit individual with normal testosterone levels would see a boost of 200% in his total or 130% in his free testosterone levels is not low, it is simply ZERO!

Notwithstanding, Tradamixina (or rather its ingredients) is actually more than just a cilialis alternative. While the latter is a short term solution to get rid of the symptoms of an underlying disease, the combination of Ecklonia Cava, tribulus, and d-glucosamine + n-acetyl-d-glucosamine could actually tackle the most frequent cause of erectile dysfunction, which is the triad of inflammation, insulin resistance and arteriosclerosis (for more details see info-box to the right).

So how does this stuff work? Although investigations into the mechanism by which the provision of Tradamaxine did work its magic was actually not part of the study, it's actually not difficult to hypothesize what may be the underlying cause of these unquestionably astonishing results. Firstly, the brown algae Ecklonia Bicyclis (better known as Ecklonia Cava!)of which each serving has 150mg has a very high content of sterols, polyphenols and tannins and is probably the main active ingredient of a formula which includes 396mg of tribulus and 144mg of d-glucosamine and n-acetyl-d-glucosamine as a 'support'. The phlototannins 7-phloro eckol and 6,6′-bieckoll that have been isolated from Ecklonia, a marine brown algae which has been used for centuries in traditional medicine in Asia, are more or less unique with respect to the potency of their antioxidant activity (Li. 2009). In conjunction with tribulus, d-glucosamine and n-acetyl-d-glucosamine, which also exhibit a certain degree of anti-inflammatory activity, a decrease in systemic inflammation is the most likely cause of the profound pro-sexual and pro-hormonal effects of this blend, which is yet by no means as unique as the producers would have it.

Bottom line: It is no coincidence that erectile dysfunction has been identified as a "harbinger of cardiovascular clinical events" (Thompson. 2005) and "a sentinel event for CAD [coronary artery disease]" (Irekpita. 2009). So if you are in the unlucky situation to suffer from vascular (and not physogenic) erectile dysfunction, and had the choice between a drug that will ameliorate the symptoms, i.e. Tadalafil, or a supplement that will treat the underyling cause, the decision for the supplement and against the lifestyle drug should be obvious, right?

Still, there is one, ... no, actually there are two things I would like to ask you, before you run all spiked up to the next best supplement shop: Firstly, how accurate would you say is the authors' claim that there was "no conflict of interest", if no one else, but the lead author of the study, has been granted a patent on the formula on April 4th, 2012 (US2012/089722 A1)? And secondly, do you really believe that it is a mere coincedence that the researchers deliberate use the hardly known appellation Ecklonia Bicyclis for a brown algae all of you probably know as Ecklonia Cava (see "Ecklonia Cava Polyphenols Help Shed Weight Even in The Presence of a Slight Caloric Surplus") throughout the whole paper without mentioning once that it is better known as "Ecklonia Cava"? I am well aware that studies are expensive and need to be financed and I am by no means suggesting that the results are - as Mark suspected - "too good to be true" (remember. the men were hypogonadal to begin with), but this paper does still have a somewhat peculiar aftertaste.

References:

• Basar MM, Atan A, Tekdogan UY. New concept parameters of RigiScan in differentiation of vascular erectile dysfunction: is it a useful test? Int J Urol. 2001 Dec;8(12):686-91.
• Iacono F, Prezioso D, Illiano E, Romeo G, Ruffo A, Amato B. Sexual asthenia: Tradamixina versus Tadalafil 5 mg daily. BMC Surg. 2012 Nov 15;12 Suppl 1:S23.
• Irekpita E, Salami TA. Erectile dysfunction and its relationship with cardiovascular risk factors and disease. Saudi Med J. 2009 Feb;30(2):184-90. 
• Li Y, Qian ZJ, Ryu B, Lee SH, Kim MM, Kim SK. Chemical components and its antioxidant properties in vitro: an edible marine brown alga, Ecklonia cava. Bioorg Med Chem. 2009 Mar 1;17(5):1963-73.
• Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005 Dec 21;294(23):2996-3002. 
• Tradapahrm Sagl. Tradamix. 2012 < http://www.tradamix.com/en/ > retrieved on 11/29/2012.