As a researcher, it seems to me that the sports nutrition industry has become obsessed with staying abreast of the latest research and innovations. Why is it that we seldom bother to venture back into the vast library of overlooked and abandoned literature that is collecting dust on the shelves – especially when there really are some lost gems out there just waiting to be re-discovered. Even though some of this research didn’t possess exactly what it takes to warrant further development at the time, upon re-visitation we might recognize potentials that could not have been previously imagined. Consider the following interesting examples:
Back in 1975, a group of researchers in Argentina wanted to examine the effects of the anti-anxiety drug Valium (diazepam) on testosterone levels. During this period, Valium use was at an all-time high and users often reported adverse effects on sexual function. Expecting to see a negative influence on testosterone levels, the researchers were quite surprised when examination of a group of men aged 35 to 55 who had been given 10-20mg of Valium daily for two weeks revealed a marked increase in plasma testosterone (average 52%). Interestingly, corticosteroid levels showed a slight decrease.
At the time there was no explanation for this phenomenon. Only years later were scientists able to discover that drugs such as Valium, known categorically as benzodiazepines, had interesting actions beyond just those demonstrated in the brain.
Most drugs work by binding to specific receptors in the body. Benzodiazepines work by binding to central benzodiazepine receptors (CBRs) found in certain parts of the brain. Here they regulate the actions of the neurotransmitter GABA, thus imparting anti-anxiety and anti-convulsant effects.
In the late 1970s though, researchers were beginning to discover that some benzodiazepines could bind to receptor sites outside of the central nervous system. These receptors are termed peripheral benzodiazepine receptors (PBRs), and they are localized with particular abundance in the adrenal glands and testis. It was later discovered that testicular PBRs were located in the outer mitochondrial membrane of leydig cells.
Leydig cells are the testosterone-producing cells of the testicles, and it is within the mitochondria of leydig cells that the actual handiwork of testosterone biosynthesis (steroidogenesis) takes place. This biosynthesis begins with the transport of cholesterol across the mitochondrial membrane to the enzyme cytochrome p-450scc located on the membrane’s inner wall. This transport is regulated by pituitary-derived luteinizing hormone (LH), the principal regulator of testosterone production. Once introduced to this enzyme, cholesterol is transformed into pregnenolone, which is then immediately transformed into progesterone, and eventually (after several more steps and intermediates) testosterone is formed.
The most important thing to understand is that the transport of cholesterol across the mitochondrial membrane is the rate-limiting step in testosterone biosynthesis. Until recently it was thought that only LH (and LH analogs like HCG) could regulate this key step. We now know that when activated by a PBR agonist such as Valium, the leydig cell PBR receptors can also open this gateway.
While Valium acts directly on the testicles to stimulate testosterone production, it also produces awful side affects and is terribly addictive. Taking Valium as a means to increase your testosterone is simply out of the question. But what if there were a substance that bound and activated the PBR but not the CBR? Such a drug would have none of the adverse mental effects (sleepiness, apathy) or addictive potential of Valium, yet would stimulate your testicles to produce testosterone.
Sorry, folks, but I know of no such chemical. It’s not to say that one could not be synthetically developed. One may already exist in nature. Certain flavonoids have been shown to bind to and activate the CBR, so it’s not inconceivable to think that a naturally occurring flavonoid could similarly activate the PBR. With literary thousands of flavonoid variants identified in nature, there certainly is a small chance that one might be found to have such activity. That is, if researchers would take the time to look.
The Amino in the Mirror
The University of Maryland was the site of research that involved the manipulation of livestock growth in a rather intriguing fashion. In the early 1990s, a research group headed by Mark Estienne examined the effects of an unusual amino acid on the feed efficiency, weight gain, and body fat deposition in chickens. They subsequently reported their findings in a patent.
N-methyl-D-aspartic acid (NMDA) is an unusual amino acid because it exists in the D configuration as opposed to the L configuration common to dietary protein aminos. In chemistry, D configured molecules are the mirror image of L configured molecules (like your right and left hands).
NMDA is known as a neuroexcitatory amino acid (NAA) and it binds to receptors in the brain called NMDA receptors. NMDA receptors play a crucial role in learning, and in the formation and retrieval of memories. NAAs such as NMDA are also known to have potent stimulatory effects upon many hormones in the body. They interact with the neurons that release hypothalamic factors such as growth hormone releasing hormone (GHRH) and luteinizing hormone releasing hormone (LHRH). These hormones subsequently go on to stimulate the release of GH and LH / testosterone. NMDA has demonstrated these hormonal effects both in-vitro and in-vivo in several different species.
In the patent granted to Estienne and company identifying the growth promoting and body composition altering properties of NMDA, GH / IGF-1 secretagogue activity was theorized as the mechanism of action. Curiously, the LH / testosterone stimulating effects were not considered by the author (probably because commercial male livestock are usually castrated anyway).
In their patent research, the authors measured IGF-1 levels in chickens and GH levels in pigs, both of which showed marked increases. The chickens also showed increased feed efficiency, increased growth rate, and decreased fat percentage upon daily feeding of NMDA. Only chickens were tested in feed experiments, but the authors speculated that NMDA might similarly benefit other species including humans.
When I first started researching NMDA, I was considering marketing it as a nutritional supplement. After delving in deeper however, a couple of things made me change my mind. First of all, I contacted the patent inventor to see if I could get some more information on NMDA. He regretfully told me that his later research failed to confirm his earlier findings, and that he had deemed the project not worthy of further pursuit. I also discovered that NMDA is potentially quite toxic and may destroy neurons in sensitive areas of the brain like the hippocampus and the basal ganglia. NMDA might also have the capacity to induce convulsions in susceptible individuals.
So what, if any, lesson was learned from this dead end research endeavor? Well, I did receive a clear reminder never to jump to conclusions based upon limited evidence – particularly never to make assumptions based solely upon patent information (which is not subject to peer review and is notoriously inaccurate). If only the marketers of the “flavor of the month” supplement 5-methyl-7-methoxy-isoflavone would have heeded such advice; perhaps consumers would have been saved from what is, in my opinion, yet another supplement disappointment.
Aminopyrine is a potent analgesic, anti-inflammatory, and anti-pyretic (fever reducer) introduced during the latter part of the 19th century. It was used extensively for many years thereafter and was considered quite a bit more effective than similar drugs of its time including aspirin.
In the early 1960s, a team of researchers at the University of Chicago Medical School discovered something interesting about aminopyrine. These researchers were studying the catabolic properties of progesterone. Since progesterone tends to induce fever in humans, the researchers decided to co-administer aminopyrine. Much to their surprise, the subjects of the study did not experience the anticipated catabolism.
Subsequent metabolic studies in humans taking aminopyrine alone have confirmed the researchers’ suspicions – aminopyrine is anabolic. The researchers found that after a normal therapeutic dose of aminopyrine, a state of positive nitrogen balance was induced. This, in conjunction with a decrease in urinary creatine and inorganic phosphorous excretion, indicated the incorporation of new muscle protein. The overall pattern of metabolic responses in the test subjects was strikingly similar to that observed when testosterone propionate was administered separately to the same individuals. The researchers specifically stated the following: “The anabolic effect with the dosage of aminopyrine employed in this study was slightly less than, but comparable to, that resulting from the intramuscular administration of 25 mg. daily of testosterone propionate.”
This all sounds very exciting but there is (as always) a downside. Aminopyrine was removed from the US market years ago because of a condition associated with its usage called agranulocytosis. Agranulocytosis is a potentially fatal disorder in which certain types of white blood cells are greatly reduced in number. Perhaps this explains why there never was any follow-up research to this study. However, as the authors pointed out, it would be interesting to see similar studies on related (but much safer) compounds, one example of which is the analgesic phenylbutazone.
Arguelles AE, Rosner, J, “Diazepam and Plasma-Testosterone Levels”, Lancet 27 (1975) 607-608
Papadopoulos V, et al., “The Peripheral-type Benzodiazepine Receptor is Functionally Linked to Leydig Cell Steroidogenesis”, J Biol Chem 265:7 (1990) 3772-3779
Estienne et al., “Use of N-Methyl-Aspartic Acid for Enhancing Growth and Altering Body Composition”, US patent 5691377
Price et al., “Acute Elevations of Serum Luteinizing Hormone Induced by Kainic Acid, M-Methyl Aspartic Acid or Homocysteic Acid”, Neuroendocrinology 26 (1978) 352-358
Ehrlich et al., “The Anabolic Influence of Aminopyrine”, Metabolism 13:9 (1964) 799-807